1,710 results on '"Triazoles pharmacokinetics"'
Search Results
2. Optimization of oral isavuconazole dose for population in special physiological or pathological state: a physiologically based pharmacokinetics model-informed precision dosing.
- Author
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Zhou J, Xu B, Zheng Y, Huang H, Wei Z, Chen S, Huang W, Liu M, Zhang Y, and Wu X
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- Humans, Administration, Oral, Child, Child, Preschool, Infant, Adult, Adolescent, Young Adult, Male, Middle Aged, Female, Aged, Invasive Fungal Infections drug therapy, Models, Biological, Triazoles pharmacokinetics, Triazoles administration & dosage, Antifungal Agents pharmacokinetics, Antifungal Agents administration & dosage, Nitriles pharmacokinetics, Nitriles administration & dosage, Pyridines pharmacokinetics, Pyridines administration & dosage
- Abstract
Objective: To recommend precision dosing and improve therapeutic efficacy against invasive fungal disease, a physiologically based pharmacokinetic model (PBPK) of oral isavuconazole (ISA) was established and used to explore its disposition across populations in different physiological and pathological states., Methods: Twenty-five pharmacokinetic (PK) studies of oral ISA were identified through a systematic search of PubMed. Concentration-time data were extracted using WebPlotDigitizer. Physiochemical parameters were obtained from published literature and DrugBank. Model development and simulation used the Simcyp population-based simulator, and visual predictive check and predictive error were used for the model evaluation. Probability of target attainment and the cumulative fraction of response analyses were performed for dose optimization., Results: The developed PBPK model was successfully validated in different populations. Most predicted concentration-time points aligned with the observed data, with acceptable predictive errors for the critical parameters. We predicted the PK profiles and parameters of ISA in a population with severe hepatic impairment (HI), a population with obesity and paediatric patients aged 1 to less than 6 years old. The probability of target attainment and cumulative fraction of response analyses indicated that the population with severe HI should have half the maintenance dose. The population with obesity and population with severe HI should have a loading dose of 300 mg every 8 h for 2 days. For paediatric patients aged 1 to less than 6 years old, a weight-based dosing regimen (5.38 mg/kg) of ISA was suggested., Conclusion: The predicted value aligns with observations, suggesting ISA's potential predictability in PK profiles for other populations. The recommended dosing regimens increase our understanding of the use of ISA in special populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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3. Individualized regimen of Posaconazole oral suspension in Chinese HSCT patients based on population pharmacokinetic model.
- Author
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Shu YS, Dong ZH, Yang YL, Li SW, Yi QY, Wang P, Shi YP, Zhang YY, and Shi HY
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- Humans, Male, Female, Adult, Middle Aged, Retrospective Studies, Adolescent, Young Adult, Administration, Oral, Models, Biological, China, Asian People, Suspensions, East Asian People, Hematopoietic Stem Cell Transplantation, Triazoles pharmacokinetics, Triazoles administration & dosage, Antifungal Agents pharmacokinetics, Antifungal Agents administration & dosage, Antifungal Agents therapeutic use
- Abstract
To establish a population pharmacokinetic (PopPK) model of posaconazole suspension in Chinese hematopoietic stem cell transplantation (HSCT) patients and to recommend an optimal dosing regimen. A single-center, retrospective, model-based study was conducted in 62 Chinese patients, including 103 with posaconazole plasma concentrations. PopPK analysis using NONMEM software. A one-compartment model of first-order elimination and absorption was in good agreement with the experimental data. Analysis of covariance showed that body weight (WT), creatinine clearance (CCR), and proton pump inhibitor (PPI) had a significant effect on the pharmacokinetics of posaconazole. The dose simulation results show that patients with CCR ≥ 90 mL/min require at least 3 mg/kg TID and 7 mg/kg BID dosing regimens for prevention and treatment, respectively. However, when combined with PPI, at least 5 mg/kg BID and 5 mg/kg TID dosing regimens are required for prevention and treatment, respectively. Regardless of whether it is used in combination with PPI or not, patients with a CCR of 60-90 mL/min can achieve PTA goals by using a 4 mg/kg BID and 4 mg/kg TID regimen for prevention and treatment, respectively. A dosing regimen of 3 mg/kg BID in patients with a CCR of 30-60 mL/min is sufficient to meet the PTA goal of prophylaxis, and the dose needs to be elevated to 4 mg/kg BID for the treatment of fungal infections, and there is no need to change the dose according to the coadministration of PPI. When the patient's CCR is less than 30 mL/min, whether or not combined with PPI, the administration regimen of 2 mg/kg BID and 3 mg/kg BID can meet the PTA goals for prevention and treatment, respectively., (© 2024. The Author(s).)
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- 2024
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4. Atropisomerism Observed in Galactose-Based Monosaccharide Inhibitors of Galectin-3 Comprising 2-Methyl-4-phenyl-2,4-dihydro-3 H -1,2,4-triazole-3-thione.
- Author
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Yoon DS, Liu C, Jalagam PR, Feng J, Wang W, Swidorski JJ, Xu L, Hartz RA, Nair SK, Beno BR, Panda M, Ghosh K, Kumar A, Sale H, Shah D, Mathur A, Ellsworth BA, Cheng D, and Regueiro-Ren A
- Subjects
- Animals, Humans, Mice, Structure-Activity Relationship, Crystallography, X-Ray, Thiones chemistry, Thiones pharmacology, Thiones chemical synthesis, Thiones pharmacokinetics, Blood Proteins metabolism, Galectins antagonists & inhibitors, Galectins metabolism, Models, Molecular, Triazoles chemistry, Triazoles pharmacology, Triazoles chemical synthesis, Triazoles pharmacokinetics, Galactose chemistry, Galactose metabolism, Galectin 3 antagonists & inhibitors, Galectin 3 metabolism
- Abstract
Galectin-3 (Gal-3) is a carbohydrate binding protein that has been implicated in the development and progression of fibrotic diseases. Proof-of-principal animal models have demonstrated that inhibition of Gal-3 is a potentially viable pathway for the treatment of fibrosis─with small molecule Gal-3 inhibitors advanced into clinical trials. We hereby report the discovery of novel galactose-based monosaccharide Gal-3 inhibitors comprising 2-methyl-4-phenyl-2,4-dihydro-3 H -1,2,4-triazole-3-thione (compound 20 ) and 4-phenyl-4 H -1,2,4-triazole (compound 15 ). Notably, hindered rotation caused by steric interaction between the 3-thione and ortho -trifluoromethyl group of compounds 20 , 21 induced formation of thermodynamically stable atropisomers. Distinct X-ray cocrystal structures of 20 and 21 were obtained, which clearly demonstrated that the configuration of 21 proscribes a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182, thereby leading to significant loss in potency. Ultimately, 20 and 15 were evaluated in mouse pharmacokinetic studies, and both compounds exhibited oral exposures suitable for further in vivo assessment.
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- 2024
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5. Effect of Hepatic Impairment on Trilaciclib Pharmacokinetics.
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Li C, Preston RA, Dumas E, Beelen A, and Marbury TC
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- Humans, Male, Female, Middle Aged, Aged, Triazoles pharmacokinetics, Triazoles administration & dosage, Liver Diseases metabolism, Protein Kinase Inhibitors pharmacokinetics, Protein Kinase Inhibitors administration & dosage, Lactones pharmacokinetics, Lactones administration & dosage, Adult, Area Under Curve, Lung Neoplasms drug therapy, Pyrimidines, Pyrroles, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents adverse effects, Antineoplastic Agents administration & dosage
- Abstract
Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4 and 6 inhibitor approved for reducing the incidence of chemotherapy-induced myelosuppression in adult patients with extensive-stage small cell lung cancer receiving a platinum/etoposide-containing or topotecan-containing regimen. No dose adjustment is recommended for participants with mild hepatic impairment (HI) based on previous population pharmacokinetic (PK) analysis. This open-label, parallel-group study examined the impact of moderate and severe HI on the PK of trilaciclib. The study employed a reduced study design. Participants with moderate (Child-Pugh B, n = 8) and severe (Child-Pugh C, n = 5) HI and matched healthy controls (n = 11) received a single intravenous dose of trilaciclib 100 mg/m
2 . The unbound fraction of trilaciclib was comparable between the HI groups and the matched healthy control group. The unbound trilaciclib extent of exposure (i.e., area under the concentration-time curve) in participants with moderate and severe HI was ∼40% and ∼60% higher, respectively, compared with healthy matched controls based on Child-Pugh classification. Ad hoc analysis using National Cancer Institute classification showed similar results. The US Food and Drug Administration-approved trilaciclib dose of 240 mg/m2 should be reduced by ∼30%, to 170 mg/m2 , for patients with moderate or severe HI., (© 2024 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2024
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6. An effective LC-MS method for the simultaneous determination of a potential anti-rheumatoid arthritis drug, carboxyamidotriazole, and its major metabolite in rat plasma.
- Author
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Lang X, Tang J, Kou Y, Xing C, Mu H, Wang Y, and Wang B
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- Animals, Rats, Male, Reproducibility of Results, Chromatography, Liquid methods, Linear Models, Antirheumatic Agents blood, Antirheumatic Agents pharmacokinetics, Limit of Detection, Sensitivity and Specificity, Liquid Chromatography-Mass Spectrometry, Triazoles blood, Triazoles pharmacokinetics, Triazoles chemistry, Rats, Sprague-Dawley, Mass Spectrometry methods
- Abstract
Carboxyamidotriazole (CAI) was previously recognized as a well-tolerated anticancer drug. It has also demonstrated significant anti-inflammatory effects in various cell and animal model experiments, prompting its investigation as a potential treatment for rheumatoid arthritis. In this study, the potential biotransformation metabolites of CAI were identified both in vitro and in vivo. A sensitive, specific, and accurate LC-MS method was developed for the quantitative analysis of CAI and its major metabolite, CAI-OH, in rat plasma. CAI, CAI-OH, and telmisartan (used as an internal standard) were separated using a Zorbax SB C
18 column. The mobile phase consisted of water (phase A, containing 0.1% formic acid) and acetonitrile (phase B, containing 0.1% formic acid) at a flow rate of 0.2 mL/min. The analytes were examined using a high-resolution mass spectrometer, with detected mass-to-charge ratios of m/z 424.01293 for CAI, m/z 440.00785 for CAI-OH, and m/z 515.24415 for telmisartan. Good linearity was observed within the range of 10-5000 ng/mL. Both inter- and intra-batch precision (relative standard deviation, %) were below 6%, and the accuracy ranged from 94.9% to 106.1%. The analytes remained stable throughout the entire experimental period. This method was successfully applied in a pharmacokinetic study of CAI following oral administration in rats., (© 2024 John Wiley & Sons Ltd.)- Published
- 2024
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7. Posaconazole-hemp seed oil loaded nanomicelles for invasive fungal disease.
- Author
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Rathee A, Solanki P, Emad NA, Zai I, Ahmad S, Alam S, Alqahtani AS, Noman OM, Kohli K, and Sultana Y
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- Animals, Rats, Triazoles administration & dosage, Triazoles pharmacokinetics, Triazoles chemistry, Triazoles pharmacology, Nanoparticles chemistry, Rats, Wistar, Candida albicans drug effects, Invasive Fungal Infections drug therapy, Aspergillus niger drug effects, Micelles, Seeds chemistry, Drug Liberation, Male, Drug Carriers chemistry, Antifungal Agents administration & dosage, Antifungal Agents pharmacokinetics, Antifungal Agents pharmacology, Antifungal Agents chemistry, Plant Oils chemistry, Plant Oils pharmacology, Plant Oils administration & dosage
- Abstract
Invasive fungal infections (IFI) pose a significant health burden, leading to high morbidity, mortality, and treatment costs. This study aims to develop and characterize nanomicelles for the codelivery of posaconazole and hemp seed oil for IFI via the oral route. The nanomicelles were prepared using a nanoprecipitation method and optimized through the Box Behnken design. The optimized nanomicelles resulted in satisfactory results for zeta potential, size, PDI, entrapment efficiency, TEM, and stability studies. FTIR and DSC results confirm the compatibility and amorphous state of the prepared nanomicelles. Confocal laser scanning microscopy showed that the optimized nanomicelles penetrated the tissue more deeply (44.9µm) than the suspension (25µm). The drug-loaded nanomicelles exhibited sustained cumulative drug release of 95.48 ± 3.27% for 24 h. The nanomicelles showed significant inhibition against Aspergillus niger and Candida albicans (22.4 ± 0.21 and 32.2 ± 0.46 mm, respectively). The pharmacokinetic study on Wistar rats exhibited a 1.8-fold increase in relative bioavailability for the nanomicelles compared to the suspension. These results confirm their therapeutic efficacy and lay the groundwork for future research and clinical applications, providing a promising synergistic antifungal nanomicelles approach for treating IFIs., (© 2024. The Author(s).)
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- 2024
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8. Pharmacokinetics of isavuconazonium sulfate and its active metabolite isavuconazole in healthy dogs.
- Author
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McQuinn E, Mochel JP, Borts D, Hanzlicek AS, Allenspach K, and Palerme JS
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- Animals, Dogs, Male, Female, Administration, Oral, Prodrugs pharmacokinetics, Cross-Over Studies, Pyridines pharmacokinetics, Pyridines administration & dosage, Nitriles pharmacokinetics, Triazoles pharmacokinetics, Triazoles administration & dosage, Antifungal Agents pharmacokinetics
- Abstract
Invasive fungal infections (IFIs) are growing in importance in veterinary and human medicine. IFIs such as aspergillosis, blastomycosis, coccidioidomycosis and histoplasmosis remain challenging to treat in dogs. Isavuconazole is a novel antifungal medication that, when compared to currently used azoles, has an expanded spectrum of antifungal activity Rudramurthy (2011), Pfaller (2013), Spec (2018), has more predictable pharmacokinetics in humans Desai (2016), Cojutti (2021) and may cause fewer side effects such as liver and renal toxicity Maertens (2016), DiPippo (2018). The pharmacokinetic profile and safety of isavuconazole in dogs has not yet been characterized. The purpose of this study was to evaluate the pharmacokinetics of isavuconazole in healthy dogs that received a single dose of the prodrug isavuconazonium sulfate. Using full crossover design, six healthy beagle dogs received isavuconazonium sulfate at a mean (+/- SD) dose of 20.6 (+/- 2.8) mg/kg orally and 21.8 (+/- 4.2) mg/kg intravenously. Plasma was collected for batched pharmacokinetic analysis of prodrug and metabolite, isavuconazole, by ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The median (Q1-Q3) maximum isavuconazole peak plasma concentration was estimated at 3,876.5 (2,811.0-4,800.0) ng/mL following oral administration, with a median (Q1-Q3) peak level at 1.3 (1.0-2.0) hours. Following intravenous administration, the median (Q1-Q3) isavuconazole peak plasma concentration was estimated at 3,221.5 (2,241.5-3,609.0) ng/mL, with a median (Q1-Q3) peak level at 0.4 (0.3-0.6) hours. The median (Q1-Q3) half-life of isavuconazole was 9.4 (7.0-12.2) hours and 14.0 (8.1-21.7) hours for oral and intravenous routes, respectively. One dog received inadvertent subcutaneous drug administration without any apparent adverse effects. Another dog experienced an anaphylactic reaction following accidental rapid drug infusion. No other drug-related adverse events were observed. At dosages used in this study, healthy dogs achieved isavuconazole plasma levels comparable to human therapeutic targets, and when properly administered the drug was well-tolerated., Competing Interests: The authors have read the journal’s policy and have the following competing interests: AH is an employee of MiraVista Diagnostics. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare., (Copyright: © 2024 McQuinn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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9. Posaconazole in paediatric malignancy and haematopoietic stem cell transplant: dosing to achieve therapeutic concentration.
- Author
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Weerdenburg H, Walker H, Curtis N, Duffull S, Haeusler G, Cole T, and Gwee A
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- Humans, Child, Immunocompromised Host, Administration, Oral, Invasive Fungal Infections prevention & control, Invasive Fungal Infections drug therapy, Child, Preschool, Hematopoietic Stem Cell Transplantation adverse effects, Antifungal Agents administration & dosage, Antifungal Agents pharmacokinetics, Antifungal Agents adverse effects, Triazoles administration & dosage, Triazoles pharmacokinetics, Triazoles adverse effects, Neoplasms
- Abstract
Objectives: Posaconazole is increasingly used for the treatment and prophylaxis of invasive fungal infections in immunocompromised children. We aimed to review evidence for paediatric posaconazole dosing regimens focusing on attainment of target concentrations and frequency of adverse effects., Methods: In May 2023, the Cochrane, Embase, MEDLINE and PubMed databases were searched for articles reporting posaconazole dosing in children with malignancy or post-haematopoietic stem cell transplantation. Studies reporting the attainment of target serum concentrations were included., Results: Overall, 24 studies were included. Eighteen studies of the oral suspension consistently reported poor attainment of target concentrations for prophylaxis (≥0.7 µg/mL, 12%-78%) despite high daily doses of 14-23 mg/kg/day (max. 1200 mg/day). Target attainment was significantly affected by gastric pH and food intake. Six studies of the delayed-release tablet (DRT) reported 58%-94% achieved concentrations ≥0.7 µg/mL, with the majority using lower doses of 4-12 mg/kg/day (max. 300 mg/day). Similarly, one study of powder for oral suspension found 67%-100% achieved target concentrations with a dose of 6 mg/kg/day (max. 300 mg/day). As expected, the IV formulation had high attainment of prophylaxis targets (81%-90%) with 6-10 mg/kg/day (max. 400 mg/day). All formulations were well tolerated, and no relationship between adverse effects and posaconazole concentrations was identified., Conclusions: The required posaconazole dose in immunocompromised children varies depending on the formulation. The IV infusion had the highest attainment of therapeutic concentration followed by the DRT and powder for suspension. By contrast, the oral suspension had low attainment of target concentrations despite higher daily doses., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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10. Integrating Full Bayesian Inference and Student's t-Distribution Method for Enhanced Outlier Handling in Caffeine Population Pharmacokinetics: Assessing Drug-Drug Interactions with Enasidenib in Relapsed or Refractory AML and MDS Patients.
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Cheng Y, Du S, Hu H, Wang X, Carayannopoulos L, and Li Y
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- Humans, Male, Middle Aged, Aged, Female, Myelodysplastic Syndromes drug therapy, Triazoles pharmacokinetics, Triazoles therapeutic use, Triazoles blood, Triazoles administration & dosage, Adult, Models, Biological, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents blood, Antineoplastic Agents therapeutic use, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase antagonists & inhibitors, Triazines, Leukemia, Myeloid, Acute drug therapy, Caffeine pharmacokinetics, Caffeine administration & dosage, Bayes Theorem, Drug Interactions, Aminopyridines pharmacokinetics, Aminopyridines therapeutic use
- Abstract
As the first-in-class, selective, and potent inhibitor of the isocitrate dehydrogenase-2 (IDH2) mutant protein, enasidenib was approved by the US Food and Drug Administration (FDA) in 2017 for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) with an IDH2 mutation. Known for its interactions with various cytochrome P450 (CYP) enzymes and transporters in vitro, a clinical pharmacokinetics (PK) trial was initiated to assess the impact of multiple doses of enasidenib on the single-dose PK of sensitive probe substrates of several cytochrome P450 enzymes and transporters. In this study, a population pharmacokinetic analysis approach was employed to address challenges posed by high, nonzero baseline caffeine concentrations. Moreover, we integrated full Bayesian inference into this approach innovatively for a more detailed understanding of parameter uncertainty and greater modeling flexibility, alongside Student's t-distribution for robust error modeling in handling the abnormal outlier caffeine concentration data observed in this trial. Our analyses demonstrated that multiple doses of enasidenib altered caffeine clearance to a clinically meaningful extent, as evidenced by an approximate 8-fold decrease. This finding led to a specific recommendation in the package insert to avoid the concurrent use of certain CYP1A2 substrates with enasidenib, unless directed otherwise in the prescribing information. Furthermore, this research underlines the technical benefits of integrating full Bayesian inference and incorporating Student's t-distribution for residual error modeling in the PK field., (© 2024, The American College of Clinical Pharmacology.)
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- 2024
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11. Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study.
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Elkayal O, Mertens B, Wauters J, Debaveye Y, Rijnders B, Verweij PE, Brüggemann RJ, Spriet I, and Dreesen E
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- Humans, Female, Middle Aged, Male, Aged, Adult, Administration, Intravenous, Computer Simulation, Intensive Care Units, Invasive Pulmonary Aspergillosis drug therapy, Triazoles pharmacokinetics, Triazoles administration & dosage, Critical Illness, Antifungal Agents pharmacokinetics, Antifungal Agents administration & dosage, Monte Carlo Method
- Abstract
Background: Posaconazole is used for the prophylaxis and treatment of invasive fungal infections in critically ill patients. Standard dosing was shown to result in adequate attainment of the prophylaxis Cmin target (0.7 mg/L) but not of the treatment Cmin target (1.0 mg/L)., Objectives: To provide an optimized posaconazole dosing regimen for IV treatment of patients with invasive pulmonary aspergillosis in the ICU., Methods: A population pharmacokinetics (popPK) model was developed using data from the POSA-FLU PK substudy (NCT03378479). Monte Carlo simulations were performed to assess treatment Cmin and AUC0-24 PTA. PTA ≥90% was deemed clinically acceptable. PopPK modelling and simulation were performed using NONMEM 7.5., Results: Thirty-one patients with intensive PK sampling were included in the PK substudy, contributing 532 posaconazole plasma concentrations. The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. Interindividual variability was estimated on clearance and volume of distribution in central and peripheral compartments. Posaconazole peripheral volume of distribution increased with bodyweight. An optimized loading regimen of 300 mg q12h and 300 mg q8h in the first two treatment days achieved acceptable PTA by Day 3 in patients <100 kg and ≥100 kg, respectively. A maintenance regimen of 400 mg q24h ensured ≥90% Cmin PTA, whereas the standard 300 mg q24h was sufficient to achieve the AUC0-24 target throughout 14 days, irrespective of bodyweight., Conclusions: We have defined a convenient, optimized IV posaconazole dosing regimen that was predicted to attain the treatment target in critically ill patients with invasive aspergillosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
- Published
- 2024
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12. Physiologically based kinetic (PBK) modeling of propiconazole using a machine learning-enhanced read-across approach for interspecies extrapolation.
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Wu Y, Sinclair G, Avanasi R, and Pecquet A
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- Animals, Humans, Risk Assessment, Models, Biological, Mice, Kinetics, Triazoles pharmacokinetics, Machine Learning, Fungicides, Industrial pharmacokinetics
- Abstract
A significant challenge in the traditional human health risk assessment of agrochemicals is the uncertainty in quantifying the interspecies differences between animal models and humans. To work toward a more accurate and animal-free risk determination, new approaches such as physiologically based kinetic (PBK) modeling have been used to perform dosimetry extrapolation from animals to humans. However, the regulatory use and acceptance of PBK modeling is limited for chemicals that lack in vivo animal pharmacokinetic (PK) data, given the inability to evaluate models. To address these challenges, this study developed PBK models in the absence of in vivo PK data for the fungicide propiconazole, an activator of constitutive androstane receptor (CAR)/pregnane X receptor (PXR). A fit-for-purpose read-across approach was integrated with hierarchical clustering - an unsupervised machine learning algorithm, to bridge the knowledge gap. The integration allowed the incorporation of a broad spectrum of attributes for analog consideration, and enabled the analog selection in a simple, reproducible, and objective manner. The applicability was evaluated and demonstrated using penconazole (source) and three pseudo-unknown target chemicals (epoxiconazole, tebuconazole and triadimefon). Applying this machine learning-enhanced read-across approach, difenoconazole was selected as the most appropriate analog for propiconazole. A mouse PBK model was developed and evaluated for difenoconazole (source), with the mode of action of CAR/PXR activation incorporated to simulate the in vivo autoinduction of metabolism. The difenoconazole mouse model then served as a template for constructing the propiconazole mouse model. A parallelogram approach was subsequently applied to develop the propiconazole rat and human models, enabling a quantitative assessment of interspecies differences in dosimetry. This integrated approach represents a substantial advancement toward refining risk assessment of propiconazole within the framework of animal alternative safety assessment strategies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors of this manuscript are employees of Syngenta Crop Protection LLC. Syngenta Crop Protection LLC is a provider of agricultural science and technology, including crop protection chemical products such as propiconazole., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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13. Hard Gelatin Capsules with Alginate-Hypromellose Microparticles as a Multicompartment Drug Delivery System for Sustained Posaconazole Release.
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Kruk K and Winnicka K
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- Drug Liberation, Delayed-Action Preparations chemistry, Antifungal Agents administration & dosage, Antifungal Agents chemistry, Antifungal Agents pharmacokinetics, Microspheres, Alginates chemistry, Gelatin chemistry, Hypromellose Derivatives chemistry, Capsules, Drug Delivery Systems methods, Triazoles chemistry, Triazoles administration & dosage, Triazoles pharmacokinetics
- Abstract
Microparticles as a multicompartment drug delivery system are beneficial for poorly soluble drugs. Mucoadhesive polymers applied in microparticle technology prolong the contact of the drug with the mucosa surface enhancing drug bioavailability and extending drug activity. Sodium alginate (ALG) and hydroxypropyl methylcellulose (hypromellose, HPMC) are polymers of a natural or semi-synthetic origin, respectively. They are characterized by mucoadhesive properties and are applied in microparticle technology. Spray drying is a technology employed in microparticle preparation, consisting of the atomization of liquid in a stream of gas. In this study, the pharmaceutical properties of spray-dried ALG/HPMC microparticles with posaconazole were compared with the properties of physical mixtures of powders with equal qualitative and quantitative compositions. Posaconazole (POS) as a relatively novel antifungal was utilized as a model poorly water-soluble drug, and hard gelatin capsules were applied as a reservoir for designed formulations. A release study in 0.1 M HCl showed significantly prolonged POS release from microparticles compared to a mixture of powders. Such a relationship was not followed in simulated vaginal fluid (SVF). Microparticles were also characterized by stronger mucoadhesive properties, an increased swelling ratio, and prolonged residence time compared to physical mixtures of powders. The obtained results indicated that the pharmaceutical properties of hard gelatin capsules filled with microparticles were significantly different from hard gelatin capsules with mixtures of powders.
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- 2024
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14. Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.
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Dinh A, Savoy JM, Kontoyiannis DP, Takahashi K, Issa GC, Kantarjian HM, DiNardo CD, and Rausch CR
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- Humans, Male, Female, Middle Aged, Aged, Voriconazole therapeutic use, Voriconazole administration & dosage, Aged, 80 and over, Drug Interactions, Adult, Antifungal Agents administration & dosage, Antifungal Agents therapeutic use, Antineoplastic Agents adverse effects, Leukemia, Myeloid, Acute drug therapy, Triazoles administration & dosage, Triazoles therapeutic use, Triazoles pharmacokinetics, Myelodysplastic Syndromes drug therapy, Pyridines administration & dosage, Pyridines therapeutic use, Pyridines pharmacokinetics, Glycine analogs & derivatives, Glycine therapeutic use, Glycine administration & dosage
- Abstract
Background: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown., Methods: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole., Results: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily., Conclusions: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib., (© 2024 American Cancer Society.)
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- 2024
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15. Development of posaconazole nanocrystalline solid dispersion: preparation, characterization and in vivo evaluation.
- Author
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Rayapolu RG, Yadav B, Apte SS, and Venuganti VVK
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- Animals, Rats, Male, Administration, Oral, Drug Compounding methods, Drug Liberation, X-Ray Diffraction methods, Freeze Drying, Chemistry, Pharmaceutical methods, Surface-Active Agents chemistry, Calorimetry, Differential Scanning methods, Nanoparticles chemistry, Triazoles pharmacokinetics, Triazoles administration & dosage, Triazoles chemistry, Antifungal Agents administration & dosage, Antifungal Agents pharmacokinetics, Rats, Wistar, Solubility, Particle Size, Biological Availability
- Abstract
Objective: Posaconazole (PCZ) is an antifungal drug, which acts by inhibiting the lanosterol-14α-demethylase enzyme. It is a biopharmaceutical classification system class II drug with its bioavailability being limited by poor aqueous solubility. The aim of this study was to improve the oral bioavailability of PCZ by preparing nanocrystalline solid dispersion (NCS)., Methods: PCZ-NCS was prepared by a combination of precipitation and high-pressure homogenization followed by freeze-drying. Several different surfactants and polymers were screened to produce NCS with smaller particle size and higher stability., Results: The optimized NCS formulation containing 0.2% Eudragit S100 and 0.2% SLS was found to provide the average particle size of 73.31 ± 4.7 nm with a polydispersity index of 0.23 ± 0.03. Scanning electron microscopy revealed the preparation of homogeneous and rounded particles. Differential scanning calorimetry and X-ray diffraction confirmed crystalline nature of NCS. Nanonization increased the saturation solubility of PCZ by about 18-fold in comparison with the neat drug. Intrinsic dissolution study showed 93% dissolution of PCZ within the first 10 min. In vivo pharmacokinetic study in Wistar rats showed that C
max and AUCtotal of PCZ-NCS increased by 2.58- and 2.64-fold compared to the marketed formulation., Conclusion: PCZ-NCS formulation presents a viable approach for enhancing the oral bioavailability of PCZ.- Published
- 2024
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16. Construction of a physiologically based pharmacokinetic model of paclobutrazol and exposure estimation in the human body.
- Author
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Li X, Lian T, Su B, Liu H, Wang Y, Wu X, He J, Wang Y, Xu Y, Yang S, and Li Y
- Subjects
- Male, Animals, Humans, Rats, Plant Growth Regulators pharmacokinetics, Adult, Solubility, Risk Assessment, Triazoles pharmacokinetics, Triazoles blood, Models, Biological, Rats, Sprague-Dawley
- Abstract
Paclobutrazol (PBZ) is a plant growth regulator that can delay plant growth and improve plant resistance and yield. Although it has been widely used in the growth of medicinal plants, human beings may take it by taking traditional Chinese medicine. There are no published studies on PBZ exposure in humans or standardized limits for PBZ in medicinal plants. We measured the solubility, oil-water partition coefficient (logP), and pharmacokinetics of PBZ in rats and established a physiologically based pharmacokinetic (PBPK) model of PBZ in rats. This was followed by extrapolation to healthy Chinese adult males as a theoretical foundation for future risk assessment of PBZ. The results showed that PBZ had low solubility and high fat solubility. Pharmacokinetic experiments showed that PBZ was absorbed rapidly but eliminated slowly in rats. On this basis, the rat PBPK model was successfully constructed and extrapolated to healthy Chinese adult males to predict the plasma concentration-time curve and exposure of PBZ in humans. The construction of the PBPK model of PBZ in this study facilitates the determination of the standard formulation limits and risk assessment of PBZ residues in medicinal plants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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17. In Silico Pharmacokinetics Evaluation of Forgiveness for Doravirine and Rilpivirine.
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Fromage Y, Jamal N, Codde C, Monchaud C, Labriffe M, Ponthier L, Marquet P, Faucher JF, and Woillard JB
- Subjects
- Humans, HIV Infections drug therapy, Models, Biological, Rilpivirine pharmacokinetics, Computer Simulation, Anti-HIV Agents pharmacokinetics, Monte Carlo Method, Pyridones pharmacokinetics, Triazoles pharmacokinetics, Triazoles blood
- Abstract
Background: This study aimed to evaluate the concentrations of rilpivirine (RLP) and doravirine (DOR) after 3 days-off using simulations from population pharmacokinetics models., Methods: The authors conducted a series of 500 sets of 10,000 Monte Carlo simulations to examine the steady-state conditions for 2 common dosage levels: 25 mg/d for RLP and 100 mg/d for DOR. These simulations were conducted under 2 scenarios: 1 without drug cessation and another after a 3-day break. The validity of the implementation was established through a comparison of median trough concentrations (C24h) with previously reported data. Subsequently, the proportion of simulated patients with C24h and C72h after 3 days-off (C72h/3do) that exceeded the inhibitory concentration 50 (IC50), 5.2 mcg/L for DOR and 20.5 mcg/L for RLP respectively, was calculated. The inhibitory quotient (IQ) was also computed, which was 6 times IC50 for DOR and 4.5 times IC50 for RLP. Finally, nomograms were constructed to estimate the probability of having C72h/3do > IC50 or > IQ for different ranges of C24h., Results: Simulated C24h median ± SD for RLP were 61.8 ± 0.4 mcg/L and for DOR 397 ± 0 mcg/L. For RLP, 99.3 ± 0.1% exceeded IC50 at C24h, 16.4 ± 0.4% at C72h/3do, and none surpassed the IQ threshold. In contrast, DOR had 100% ± 0% above IC50 at C24h, 93.6 ± 0.2% at C72h/3do, and 58.6 ± 0.5% exceeded the IQ., Conclusions: These findings suggest that treatment with DOR may offer a more forgiving therapeutic profile than RLP, given the larger proportion of patients achieving effective drug exposure with DOR. However, it is important to acknowledge a significant limitation of this study, namely, the assumption that drug concentration is a perfect surrogate for drug effectiveness., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2024
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18. Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions.
- Author
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Bergmann F, Wölfl-Duchek M, Jorda A, Al Jalali V, Leutzendorff A, Sanz-Codina M, Gompelmann D, Trimmel K, Weber M, Eberl S, Van Os W, Minichmayr IK, Reiter B, Stimpfl T, Idzko M, and Zeitlinger M
- Subjects
- Humans, Male, Adult, Prospective Studies, Female, Infusions, Intravenous, Young Adult, Microbial Sensitivity Tests, Middle Aged, Aspergillus fumigatus drug effects, Aspergillus flavus drug effects, Bronchoalveolar Lavage Fluid chemistry, Leukocytes, Mononuclear metabolism, Leukocytes, Mononuclear drug effects, Triazoles pharmacokinetics, Triazoles administration & dosage, Pyridines pharmacokinetics, Pyridines administration & dosage, Antifungal Agents pharmacokinetics, Antifungal Agents administration & dosage, Healthy Volunteers, Nitriles pharmacokinetics, Nitriles administration & dosage
- Abstract
Background: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited., Materials and Methods: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus., Results: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ± 1.68 mg/L (mean ± SD) and 106 ± 32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ± 0.03, 0.94 ± 0.46 and 27.1 ± 17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ± 32.1, 1.68 ± 0.72, 22.6 ± 11.0 and 650 ± 426 mg·h/L, respectively., Conclusion: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)
- Published
- 2024
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19. Personalized Antifungal Therapy Through Model-Informed Precision Dosing of Posaconazole.
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Jansen AME, Snijdelaar K, Keizer RJ, Spriet I, Dreesen E, Brüggemann RJM, and Ter Heine R
- Subjects
- Humans, Male, Female, Middle Aged, Adult, Administration, Oral, Aged, Prospective Studies, Dose-Response Relationship, Drug, Young Adult, Antifungal Agents administration & dosage, Antifungal Agents pharmacokinetics, Triazoles administration & dosage, Triazoles pharmacokinetics, Triazoles blood, Models, Biological, Precision Medicine methods
- Abstract
Background and Objective: Posaconazole is a pharmacotherapeutic pillar for prophylaxis and treatment of invasive fungal diseases. Dose individualization is of utmost importance as achieving adequate antifungal exposure is associated with improved outcome. This study aimed to select and evaluate a model-informed precision dosing strategy for posaconazole., Methods: Available population pharmacokinetic models for posaconazole administered as a solid oral tablet were extracted from the literature and evaluated using data from a previously published prospective study combined with data collected during routine clinical practice. External evaluation and selection of the most accurate and precise model was based on graphical goodness-of-fit and predictive performance. Measures for bias and imprecision included mean percentage error (MPE) and normalized relative root mean squared error (NRMSE), respectively. Subsequently, the best-performing model was evaluated for its a posteriori fit-for-purpose and its suitability in a limited sampling strategy., Results: Seven posaconazole models were evaluated using 764 posaconazole plasma concentrations from 143 patients. Multiple models showed adequate predictive performance illustrated by acceptable goodness-of-fit and MPE and NRMSE below ± 10% and ± 25%, respectively. In the fit-for-purpose analysis, the selected model showed adequate a posteriori predictive performance. Bias and imprecision were lowest in the presence of two prior measurements. Additionally, this model showed to be useful in a limited sampling strategy as it adequately predicted total posaconazole exposure from one (non-)trough concentration., Conclusion: We validated an MIPD strategy for posaconazole for its fit-for-purpose. Thereby, this study is an important first step towards MIPD-supported posaconazole dosage optimization with the goal to improve antifungal treatment in clinical practice., (© 2024. The Author(s).)
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- 2024
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20. Quantification of the aromatase inhibitor letrozole and its carbinol metabolite in mouse plasma by UHPLC-MS/MS.
- Author
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Taheri H, Jin Y, Ahmed E, Hu P, Li Y, Sparreboom A, and Hu S
- Subjects
- Animals, Mice, Chromatography, High Pressure Liquid methods, Reproducibility of Results, Linear Models, Limit of Detection, Female, Male, Letrozole blood, Letrozole pharmacokinetics, Letrozole chemistry, Tandem Mass Spectrometry methods, Aromatase Inhibitors blood, Aromatase Inhibitors pharmacokinetics, Aromatase Inhibitors chemistry, Nitriles blood, Nitriles pharmacokinetics, Triazoles blood, Triazoles pharmacokinetics, Triazoles chemistry
- Abstract
A liquid chromatography - electrospray ionization-mass spectrometry (LC-ESI-MS) method was developed for the quantification of letrozole, a third-generation aromatase inhibitor, and its main carbinol metabolite (CM) in support of murine pharmacokinetic studies. Using polarity switching, simultaneous ESI-MS measurement of letrozole and CM was achieved in positive and negative mode, respectively. The assay procedure involved a one-step protein precipitation and extraction of all analytes from mouse plasma requiring only 5 μL of sample. Separation was optimized on an Accucore aQ column with gradient elution at a flow rate of 0.4 mL/min in 5 min. Two calibration curves per day over four consecutive measurement days showed satisfactory linear responses (r
2 > 0.99) over concentration ranges of 5-1000 ng/mL and 20-2000 ng/mL for letrozole and CM, respectively. No matrix effect was found, and the mean extraction recoveries were 103-108 % for letrozole and 99.8-107 % for CM. Precision and accuracy within a single run and over four consecutive measurement days were verified to be within acceptable limits. Application of the developed method to preclinical pharmacokinetic studies in mice receiving oral letrozole at a dose 1 or 10 mg/kg revealed that the systemic exposure to letrozole was dose-, formulation-, and strain-dependent. These findings may inform the future design of preclinical studies aimed at refining the pharmacological profile of this clinically important drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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21. Comment on "Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies" and "High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints".
- Author
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Kong L, Alffenaar JC, and Stocker SL
- Subjects
- Humans, Dose-Response Relationship, Drug, Critical Illness, Pyridines pharmacokinetics, Pyridines administration & dosage, Nitriles pharmacokinetics, Nitriles administration & dosage, Nitriles pharmacology, Triazoles pharmacokinetics, Triazoles administration & dosage, Triazoles pharmacology, Antifungal Agents pharmacokinetics, Antifungal Agents administration & dosage, Antifungal Agents pharmacology
- Published
- 2024
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22. Subtherapeutic triazole concentrations as result of a drug-drug interaction with lumacaftor/ivacaftor.
- Author
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Smeets TJL, van der Sijs H, Janssens HM, Ruijgrok EJ, and de Winter BCM
- Subjects
- Humans, Retrospective Studies, Male, Female, Child, Adolescent, Adult, Chloride Channel Agonists pharmacokinetics, Voriconazole pharmacokinetics, Itraconazole pharmacokinetics, Itraconazole administration & dosage, Drug Interactions, Cystic Fibrosis drug therapy, Cystic Fibrosis microbiology, Quinolones pharmacokinetics, Drug Combinations, Triazoles pharmacokinetics, Triazoles administration & dosage, Benzodioxoles pharmacokinetics, Aminophenols pharmacokinetics, Aminopyridines pharmacokinetics, Antifungal Agents pharmacokinetics, Antifungal Agents administration & dosage
- Abstract
Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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23. Discovery of Novel Aryl Triazolone Dihydropyridines (ATDPs) Targeting Highly Conserved Residue W229 as Promising HIV-1 NNRTIs.
- Author
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Sun Y, Zhou Z, Wang N, Zhao F, Liu Y, Xu X, Wang X, Gou Z, De Clercq E, Pannecouque C, Zhan P, Kang D, and Liu X
- Subjects
- Humans, Structure-Activity Relationship, HIV Reverse Transcriptase antagonists & inhibitors, HIV Reverse Transcriptase metabolism, Animals, Male, Drug Discovery, Molecular Structure, Mice, HIV-1 drug effects, Triazoles chemistry, Triazoles pharmacology, Triazoles pharmacokinetics, Anti-HIV Agents pharmacology, Anti-HIV Agents chemistry, Anti-HIV Agents chemical synthesis, Anti-HIV Agents pharmacokinetics, Reverse Transcriptase Inhibitors pharmacology, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors pharmacokinetics, Molecular Docking Simulation, Dihydropyridines chemistry, Dihydropyridines pharmacology, Dihydropyridines pharmacokinetics
- Abstract
NNRTI is an important component of the highly active antiretroviral therapy (HAART), but the rapid emergence of drug resistance and poor pharmacokinetics limited their clinical application. Herein, a series of novel aryl triazolone dihydropyridines (ATDPs) were designed by structure-guided design with the aim of improving drug resistance profiles and pharmacokinetic profiles. Compound 10n (EC
50 = 0.009-17.7 μM) exhibited the most active potency, being superior to or comparable to that of doravirine (DOR) against the whole tested viral panel. Molecular docking was performed to clarify the reason for its higher resistance profiles. Moreover, 10n demonstrated excellent pharmacokinetic profile ( T1/2 = 5.09 h, F = 108.96%) compared that of DOR ( T1/2 = 4.4 h, F = 57%). Additionally, 10n was also verified to have no in vivo acute or subacute toxicity (LD50 > 2000 mg/kg), suggesting that 10n is worth further investigation as a novel oral NNRTIs for HIV-1 therapy.- Published
- 2024
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24. Effect of Daridorexant on the Pharmacokinetics of Midazolam, and on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects.
- Author
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Zenklusen I, Dingemanse J, Reh C, Gehin M, and Kaufmann P
- Subjects
- Humans, Male, Adult, Young Adult, Healthy Volunteers, Triazoles pharmacokinetics, Triazoles administration & dosage, Triazoles pharmacology, Prospective Studies, Orexin Receptor Antagonists pharmacokinetics, Orexin Receptor Antagonists pharmacology, Orexin Receptor Antagonists administration & dosage, Area Under Curve, Drug Interactions, Midazolam pharmacokinetics, Midazolam administration & dosage, Warfarin pharmacokinetics, Warfarin administration & dosage, Warfarin pharmacology, Imidazoles, Pyrrolidines
- Abstract
Background and Objectives: Daridorexant, a dual orexin receptor antagonist was recently approved for the treatment of insomnia at doses up to 50 mg once per night. This study investigated the effect of single-dose and multiple-dose daridorexant 50 mg at steady state on the pharmacokinetics (PK) of the cytochrome P450 (CYP) 3A4-sensitive substrate midazolam, and the effect of single-dose daridorexant 50 mg on the PK and pharmacodynamics (PD) of the CYP2C9-sensitive substrate warfarin., Methods: In this prospective, single-center, open-label, fixed-sequence, phase I, drug-drug interaction study, 18 healthy male subjects sequentially received Treatment A, B, and C in three periods. Treatment A consisted of a single oral concomitant administration of midazolam 2 mg and warfarin 25 mg on day 1 of the first period. Treatment B consisted of one oral administration of daridorexant 50 mg followed 1 h later by a single oral dose of midazolam 2 mg concomitantly with a single oral dose of warfarin 25 mg on day 1 and a once-daily oral administration of daridorexant 50 mg for 6 days of the second period. Treatment C consisted of a single oral administration of daridorexant 50 mg at steady state followed 1 h later by a single oral administration of midazolam 2 mg on day 1 of the third period. Blood samples were assessed for midazolam and S-warfarin PK, and PD (international normalized ratio and factor VII). Noncompartmental PK parameters and PD variables were evaluated with geometric mean ratios and 90% confidence intervals of Treatment B/A versus C/A for midazolam, and treatment B/A for warfarin. Safety and tolerability of each treatment were also assessed., Results: Midazolam maximum plasma concentration (C
max ) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24 ) were 1.13- and 1.42-fold higher, respectively, after single-dose administration of daridorexant 50 mg compared to administration of midazolam alone, while Cmax and AUC0-24 were 1.12- and 1.35-fold higher, respectively, after administration of daridorexant 50 mg once daily at steady state. Terminal half-life and time to maximum plasma concentration were comparable between treatments. Daridorexant had no influence on the PK and PD of warfarin. All treatments were safe and well tolerated., Conclusions: Daridorexant at 50 mg is classified as a weak CYP3A4 inhibitor after single- and multiple-dose administration once daily at steady state. Daridorexant 50 mg did not induce CYP3A4 activity or inhibit CYP2C9 activity., Clinical Trial Registration: This trial (NCT05480488) was registered on 29 July, 2022., (© 2024. The Author(s).)- Published
- 2024
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25. Optimized Antifungal Therapy for Chronic Pulmonary Aspergillosis.
- Author
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Yagi Y, Yamagishi Y, and Hamada Y
- Subjects
- Humans, Chronic Disease, Aspergillus drug effects, Pyridines therapeutic use, Pyridines administration & dosage, Pyridines pharmacokinetics, Nitriles therapeutic use, Nitriles administration & dosage, Nitriles pharmacokinetics, Drug Resistance, Fungal, Antifungal Agents pharmacokinetics, Antifungal Agents administration & dosage, Antifungal Agents therapeutic use, Pulmonary Aspergillosis drug therapy, Triazoles pharmacokinetics, Triazoles administration & dosage, Triazoles therapeutic use
- Abstract
Chronic pulmonary aspergillosis (CPA) represents a spectrum of lung disorders caused by local proliferation of Aspergillus hyphae in individuals with non-systemic or mildly systemic immunodepression or altered pulmonary integrity due to underlying disease. While long-term systemic antifungal treatment is still the mainstay for management, surgery is considered mainly in rarer invasive disease manifestations such as sinusitis and osteomyelitis. Optimal application of existing antifungal agents with suitable pharmacokinetic properties is important for the treatment of diseases such as CPA, which requires long-term use. Appropriate management of side effects by therapeutic drug monitoring, maintenance of adherence, and assessment of drug resistance to Aspergillus can provide safe and effective treatment in the future. Most available antifungal agents for the management of mycoses in humans have disadvantages that can limit their use in clinical practice. By contrast, second generation antifungals such as triazoles have advantages of extended antifungal spectrum and availability in both oral and intravenous formulations. Isavuconazole, a new extended spectrum triazole, has been shown to be effective against Aspergillus. The safety profile and excellent pharmacokinetic characteristics of isavuconazole make it an attractive option for treatment of invasive fungal infections including CPA. With this drug now available in Japan, new evidence is expected to expand treatment options. This review focuses on the selection of antifungal agents based on national and international guidelines and the characteristics of each agent for their appropriate use in CPA.
- Published
- 2024
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26. Synthesis, Molecular Docking, and Biological Evaluation of Novel Indole-triazole Conjugates.
- Author
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Berwal P, Rohilla S, Mathur N, and Rani K
- Subjects
- Microbial Sensitivity Tests, Structure-Activity Relationship, Molecular Docking Simulation, Triazoles pharmacology, Triazoles chemistry, Triazoles chemical synthesis, Triazoles pharmacokinetics, Indoles pharmacology, Indoles chemistry, Indoles chemical synthesis, Indoles pharmacokinetics, Antioxidants pharmacology, Antioxidants chemistry, Antioxidants chemical synthesis, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents chemistry, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents pharmacokinetics, DNA Gyrase metabolism
- Abstract
Background: Indole-triazole conjugates have emerged as promising candidates for new drug development. Their distinctive structural characteristics, coupled with a wide array of biological activities, render them a captivating and promising field of research for the creation of novel pharmaceutical agents., Objective: This study aimed to synthesize indole-triazole conjugates to investigate the influence of various substituents on the functional characteristics of indole-triazole hybrids. It also aimed to study the binding modes of new hybrids with the DNA Gyrase using molecular docking studies., Methods: A new set of indole-triazole hybrids was synthesized and characterized using various physicochemical and spectral analyses. All hybrids underwent in-silico pharmacokinetic prediction studies. The antimicrobial efficacy of the hybrids was assessed using tube dilution and agar diffusion methods. Additionally, the in-vitro antioxidant activity of synthesized compounds was determined using the 1,1-diphenyl-2-picryl-hydrazyl free radical scavenging assay. Furthermore, in silico molecular docking studies were performed to enhance our comprehension of how the synthesized compounds interact at the molecular level with DNA gyrase., Results: Pharmacokinetic predictions of synthesized hybrids indicated favourable pharmacokinetic profiles, and none of the compounds violated the Lipinski rule of five. Notably, compound 6, featuring a cyclohexanol substituent, demonstrated superior antimicrobial and antioxidant activity (EC
50 value = 14.23 μmol). Molecular docking studies further supported the in vitro antioxidant and antimicrobial findings, revealing that all compounds adeptly fit into the binding pocket of DNA Gyrase and engaged in interactions with crucial amino acid residues., Conclusion: In summary, our research underscores the efficacy of molecular hybridization in shaping the physicochemical, pharmacokinetic, and biological characteristics of novel indole-triazole derivatives., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)- Published
- 2024
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27. Deferasirox: A comprehensive drug profile.
- Author
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Kabil MF and Nasr M
- Subjects
- Humans, Deferasirox pharmacology, Deferasirox therapeutic use, Triazoles therapeutic use, Triazoles pharmacokinetics, Iron Chelating Agents pharmacology, Iron Chelating Agents therapeutic use, Iron Chelating Agents metabolism, Iron metabolism, Iron therapeutic use, Benzoates pharmacology, Benzoates therapeutic use, Benzoates metabolism, Iron Overload drug therapy
- Abstract
Deferasirox is an iron-chelating drug developed by Novartis company for treatment of diseases accompanied by chronic iron overload; such as β-thalassemia or sickle cell diseases. Owing to its advantages such as high affinity, specificity and wide therapeutic window, it is considered as first line treatment. The current chapter describes the physicochemical characteristics, mode of action, pharmacokinetics, therapeutic applications and synthetic methods for deferasirox. Moreover, it includes Fourier transform infrared spectrometry (FTIR) and nuclear magnetic resonance spectroscopy (NMR) analysis for its functional groups. In addition, the selected analytical methods are summarized to aid the analysts in their routine analysis of deferasirox., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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28. High Variability in Isavuconazole Unbound Fraction in Clinical Practice: A Call to Reconsider Pharmacokinetic/Pharmacodynamic Targets and Breakpoints.
- Author
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Jansen AME, Ter Heine R, Verweij PE, and Brüggemann RJM
- Subjects
- Humans, Protein Binding, Triazoles pharmacokinetics, Nitriles pharmacokinetics, Pyridines therapeutic use, Pyridines pharmacokinetics
- Abstract
Isavuconazole exposure-response relationships have been studied with a focus on total rather than unbound exposure, assuming a constant unbound fraction of 1%. We observed a median (range) unbound fraction of 1.59% (0.42-5.30%) in patients. This highly variable protein binding asks for re-evaluation of current pharmacokinetic and pharmacodynamic targets for isavuconazole., (© 2023. The Author(s).)
- Published
- 2023
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29. Meta-pharmacokinetic analysis of posaconazole following dosing of oral suspension, delayed-release tablet, and intravenous infusion in patients vs. healthy volunteers: Impact of clinical characteristics and race.
- Author
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Chen L, Krekels EHJ, Dong Y, Chen L, Maertens JA, Blijlevens NMA, Knibbe CAJ, and Brüggemann RJ
- Subjects
- Humans, Infusions, Intravenous, Tablets, Biological Availability, Suspensions, Administration, Oral, Antifungal Agents, Triazoles pharmacokinetics
- Abstract
Objectives: To investigate the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics in patients using an integrated population pharmacokinetic model for posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous (IV) infusion that was developed in healthy volunteers (HV)., Methods: 1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three posaconazole formulations were pooled with 3898 concentrations from 182 HV. Clinical characteristics were tested for significance. The impact of Chinese race was assessed using 292 opportunistic samples from 80 Chinese patients receiving SUS., Results: Bioavailability of SUS (F
sus ) in patients decreased from 38.2% to 24.6% when the dose was increased from 100 mg to 600 mg. Bioavailability of DR-tablet (Ftab ) was 59% regardless of dose. Mucositis, diarrhoea, administration through a nasogastric tube, and concomitant use of proton pump inhibitors or metoclopramide reduced Fsus by 61%, 36%, 44%, 48%, and 29%, respectively, putting patients with these characteristics at increased risk of inadequate exposure. Clearance decreased from 7.0 to 5.1 L/h once albumin levels were <30 g/L. Patients showed an 84.4% larger peripheral volume of distribution (Vp ) and 67.5% lower intercompartmental clearance (Q) compared with HV. No racial difference could be identified., Conclusions: Pharmacokinetics of posaconazole in patients differ considerably to those in HV, with altered Fsus that is also impacted by clinical covariates, an Ftab similar to fasted conditions in HV, and altered parameters for clearance, Vp , and Q. There was no evidence to indicate that Chinese patients require a different dose to Caucasian patients., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2023
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30. Population Pharmacokinetics of Total and Unbound Isavuconazole in Critically Ill Patients: Implications for Adaptive Dosing Strategies.
- Author
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Jansen AME, Mertens B, Spriet I, Verweij PE, Schouten J, Wauters J, Debaveye Y, Ter Heine R, and Brüggemann RJM
- Subjects
- Adult, Humans, Prospective Studies, Triazoles pharmacokinetics, Anti-Bacterial Agents pharmacokinetics, Critical Illness therapy
- Abstract
Background and Objectives: Isavuconazole is a broad-spectrum antifungal agent for the management of invasive fungal disease. Optimised drug exposure is critical for patient outcomes, specifically in the critically ill population. Solid information on isavuconazole pharmacokinetics including protein binding in patients in the intensive care unit is scarce. We aimed to describe the total and unbound isavuconazole pharmacokinetics and subsequently propose a dosage optimisation strategy., Methods: A prospective multi-centre study in adult intensive care unit patients receiving isavuconazole was performed. Blood samples were collected on eight timepoints over one dosing interval between days 3-7 of treatment and optionally on one timepoint after discontinuation. Total and unbound isavuconazole pharmacokinetics were analysed by means of population pharmacokinetic modelling using NONMEM. The final model was used to perform simulations to assess exposure described by the area under the concentration-time curve and propose an adaptive dosing approach., Results: Population pharmacokinetics of total and unbound isavuconazole were best described by an allometrically scaled two-compartment model with a saturable protein-binding model and interindividual variability on clearance and the maximum binding capacity. The median (range) isavuconazole unbound fraction was 1.65% (0.83-3.25%). After standard dosing, only 35.8% of simulated patients reached a total isavuconazole area under the concentration-time curve > 60 mg·h/L at day 14. The proposed adaptive dosing strategy resulted in an increase to 62.3% of patients at adequate steady-state exposure., Conclusions: In critically ill patients, total isavuconazole exposure is reduced and protein binding is highly variable. We proposed an adaptive dosing approach to enhance early treatment optimisation in this high-risk population., Clinical Trial Registration: ClinicalTrials.gov identifier: NCT04777058., (© 2023. The Author(s).)
- Published
- 2023
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31. Bronchopulmonary penetration of isavuconazole in lung transplant recipients.
- Author
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Caballero-Bermejo AF, Darnaude-Ximénez I, Aguilar-Pérez M, Gomez-Lopez A, Sancho-López A, López García-Gallo C, Díaz Nuevo G, Diago-Sempere E, Ruiz-Antorán B, Avendaño-Solá C, and Ussetti-Gil P
- Subjects
- Humans, Bronchoalveolar Lavage Fluid, Triazoles pharmacokinetics, Transplant Recipients, Lung surgery
- Abstract
Isavuconazole's (ISA) pharmacokinetics was studied among lung transplant recipients to evaluate its bronchopulmonary penetration. This study included 13 patients and showed mean serum concentrations of 3.30 (standard deviation [SD] 0.45), 5.12 (SD 1.36), and 6.31 (SD 0.95) at 2 h, 4 h, and 24 h respectively. Mean concentrations in the epithelial lining fluid were 0.969 (SD 0.895), 2.141 (SD 1.265), and 2.812 (SD 0.693) at the same time points. ISA is a drug with a tolerable safety profile that achieves adequate concentrations in the lung., Competing Interests: The authors declare no conflict of interest.
- Published
- 2023
- Full Text
- View/download PDF
32. Effects of the CYP3A inhibitors, voriconazole, itraconazole, and fluconazole on the pharmacokinetics of osimertinib in rats.
- Author
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Lou Y, Song F, Cheng M, Hu Y, Chai Y, Hu Q, Wang Q, Zhou H, Bao M, Gu J, and Zhang Y
- Subjects
- Male, Rats, Animals, Voriconazole pharmacology, Fluconazole pharmacology, Antifungal Agents pharmacology, Cytochrome P-450 CYP3A Inhibitors, Tandem Mass Spectrometry, ErbB Receptors, Rats, Sprague-Dawley, Protein Kinase Inhibitors, Mutation, Triazoles pharmacokinetics, Itraconazole pharmacology, Lung Neoplasms drug therapy
- Abstract
Background: Osimertinib, as third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line treatment approved to treat advanced T790M mutation-positive tumors. Triazole antifungals are therapeutic drugs for cancer patients to reduce the risk of opportunistic fungal infections. Our objective was to investigate whether three triazole antifungals (voriconazole, itraconazole, and fluconazole) could change the pharmacokinetics of osimertinib in rats., Methods: The adult male Sprague-Dawley rats were randomly divided into four groups ( n = 6): control (0.3% CMC-Na), and voriconazole (20 mg/kg), itraconazole (20 mg/kg), or fluconazole (20 mg/kg) combined with osimertinib (10 mg/kg) group. Tail vein blood samples were collected into heparin tubes at various time points within 0-48 h after osimertinib administration. Osimrtinib's plasma concentration was detected using HPLC-MS/MS system equipped with a Waters XBridge C
18 column, with the mobile phase consisting of acetonitrile and 0.2% formic acid water at a flow rate of 0.5 mL/min., Results: Co-administration with voriconazole or fluconazole increased the Cmax of osimertinib by 58.04% and 53.45%, respectively; the AUC0-t increased by 62.56% and 100.98%, respectively. However, when co-administered with itraconazole, the Cmax and AUC0-t of osimertinib only increased by 13.91% and 34.80%, respectively., Conclusions: Our results revealed that the pharmacokinetics of osimertinib were significantly changed by voriconazole and fluconazole in rats, whereas it was slightly affected by itraconazole. This work will contribute to a more comprehensive understanding of the pharmacokinetic properties of osimertinib when co-administered with triazole antifungals., Competing Interests: The authors declare there are no competing interests., (©2023 Lou et al.)- Published
- 2023
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- View/download PDF
33. Population Pharmacokinetics of Posaconazole in Immune-Compromised Children and Assessment of Target Attainment in Invasive Fungal Disease.
- Author
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McCann S, Sinha J, Wilson WS, McKinzie CJ, Garner LM, and Gonzalez D
- Subjects
- Adult, Humans, Child, Retrospective Studies, Administration, Oral, Antifungal Agents pharmacokinetics, Triazoles pharmacokinetics, Tablets, Suspensions, Invasive Fungal Infections drug therapy
- Abstract
Background and Objective: Posaconazole (PSZ) is a triazole antifungal for the management of invasive fungal disease (IFD) in adults and children. Although PSZ is available as an intravenous (IV) solution, oral suspension (OS) and delayed-release tablets (DRTs), OS is the preferred formulation for pediatric use because of potential safety concerns associated with an excipient in the IV formulation and difficulty in swallowing intact tablets by children. However, poor biopharmaceutical characteristics of the OS formulation leads to an unpredictable dose-exposure profile of PSZ in children, potentially risking therapeutic failure. The goal of this study was to characterize the population pharmacokinetics (PK) of PSZ in immunocompromised children and assess therapeutic target attainment., Methods: Serum concentrations of PSZ were collected retrospectively from records of hospitalized patients. A population PK analysis was performed in a nonlinear mixed-effects modeling framework with NONMEM (v7.4). The PK parameters were scaled to body weight, then potential covariate effects were assessed. The final PK model was used to evaluate recommended dosing schemes through simulation of target attainment (as a percentage of the population having steady-state trough concentrations above the recommended target) using Simulx (v2021R1)., Results: Repeated measurement data of 202 serum concentrations of total PSZ were acquired from 47 immunocompromised patients between 1 and 21 years of age receiving PSZ either intravenously or orally, or both. A one-compartment PK model with first-order absorption and linear elimination best fit the data. The estimated absolute bioavailability (95% confidence interval) for suspension (F
s ) was 16% (8-27%), which was significantly lower than the reported tablet bioavailability (Ft ) [67%]. Fs was reduced by 62% and 75% upon concomitant administration with pantoprazole (PAN) and omeprazole (OME), respectively. Famotidine resulted in a reduction of Fs by only 22%. Both fixed dosing and weight-based adaptive dosing provided adequate target attainment when PAN or OME were not coadministered with the suspension., Conclusions: The results of this study revealed that both fixed and weight-based adaptive dosing schemes can be appropriate for target attainment across all PSZ formulations, including suspension. Additionally, covariate analysis suggests that concomitant proton pump inhibitors should be contraindicated during PSZ suspension dosing., (© 2023. The Author(s).)- Published
- 2023
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- View/download PDF
34. Population Pharmacokinetics, Exposure-Safety, and Probability of Target Attainment Analyses for Isavuconazole in Japanese Patients With Deep-Seated Mycoses.
- Author
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Shirae S, Tsuruya Y, Kozaki T, Mizuhata J, and Ose A
- Subjects
- Humans, Animals, Mice, Triazoles pharmacokinetics, Probability, East Asian People, Mycoses drug therapy
- Abstract
Isavuconazonium sulfate is the water-soluble prodrug of the novel, broad-spectrum, triazole antifungal agent isavuconazole. Its pharmacokinetics (PK) and exposure-response relationship have been well investigated, but not in a Japanese patient population. The objectives of this analysis were to (1) develop a population PK model for Japanese patients with deep-seated mycoses and healthy subjects, and to identify significant covariates; (2) determine the probability of PK-pharmacodynamic (PK-PD) target attainment in Japanese patients by a clinical dosing regimen; and (3) evaluate the exposure-safety relationship of isavuconazole in Japanese patients. Data from 2 phase 1 studies and 1 phase 3 study in Japanese patients were pooled to develop the population PK model using NONMEM. The PK of isavuconazole in Japanese patients was best described as a 2-compartment model with a Weibull absorption function and first-order elimination. The identified covariates on clearance were creatinine clearance and lean body mass. The probability of target attainment showed that >90% of simulated Japanese patients would achieve the PK-PD target, an exposure index corresponding to 50% survival of nonneutropenic infected mice, with minimal inhibitory concentration values of ≤1 mg/L according to Clinical and Laboratory Standards Institute methodology and of ≤2 mg/L according to European Committee on Antimicrobial Susceptibility Testing methodology by the clinical dosing regimen. No apparent relationships were found for any of the exposure parameters of isavuconazole with any assessed safety end points in Japanese patients. Taken together, the clinical dosing regimen is appropriate for the treatment of Japanese patients with deep-seated mycoses., (© 2023 Asahi Kasei Pharma Corporation. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)
- Published
- 2023
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- View/download PDF
35. Filgotinib in rheumatoid arthritis.
- Author
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Westhovens R
- Subjects
- Humans, Pyridines pharmacokinetics, Pyridines therapeutic use, Triazoles pharmacokinetics, Triazoles therapeutic use, Antirheumatic Agents therapeutic use, Antirheumatic Agents pharmacology, Arthritis, Rheumatoid drug therapy, Janus Kinase Inhibitors therapeutic use
- Abstract
Introduction: Rheumatoid Arthritis (RA) remains a challenge for rheumatologists and patients despite implementation of intensive treat-to-target strategies in shared decision with patients and an increasing availability of drugs. Janus kinase inhibitors (JAKi) are a new generation of oral targeted drugs. Filgotinib preferentially inhibits JAK1 and is the latest JAKi to be approved for use in RA., Areas Covered: This narrative review focuses on drug characteristics, efficacy, and safety of filgotinib in patients with RA, summarizing available literature. Trial data are detailed, put into perspective for practice and discussed in regulatory perspective., Expert Opinion: Preclinical studies demonstrate preferential inhibition of JAK1 and a promising pharmacokinetic profile with few drug-drug interactions. Increase in hemoglobin in line with preferential inhibition of JAK1 over JAK2 is seen in early-phase clinical trials. A phase III program demonstrates efficacy in several disease stages, numerically higher with 200 mg versus 100 mg daily. In the overall RA population such dose-related effect is not observed for safety except for herpes zoster and increases in lipids and creatine phosphokinase. This reassuring safety profile is to be confirmed in future practice. It also needs to be unraveled if JAK1 preferential inhibition plays a key role in this safety profile.
- Published
- 2023
- Full Text
- View/download PDF
36. Demonstration of the Rationale for Therapeutic Drug Monitoring of Isavuconazole: A Case Report with a Lung Transplant Recipient.
- Author
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Dvořáčková E, Zajacová A, Havlín J, Klapková E, Lischke R, Slanař O, and Šíma M
- Subjects
- Humans, Transplant Recipients, Drug Monitoring, Triazoles therapeutic use, Triazoles pharmacokinetics, Lung, Aspergillosis drug therapy, Mucormycosis diagnosis, Mucormycosis drug therapy
- Abstract
Mucormycosis is a rare invasive fungal disease diagnosed in immunocompromised patients, including those with diabetes or iron overload, and in patients treated for hematological malignancies or after transplantation. Isavuconazole is a triazole antifungal effective against Mucorales with good tolerability, but with potential for relatively high interindividual variability in pharmacokinetics. This report demonstrates the case of a lung transplant recipient treated with isavuconasole that exhibits a very long elimination half-life of 159 hours, and discusses the practical implications of this finding for dosage adjustment and need for therapeutic drug monitoring.
- Published
- 2023
- Full Text
- View/download PDF
37. [Comparative clinical study of pharmacokinetics and bioequivalence of Relonova and Maxalt].
- Author
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Khokhlov AL and Leykin ZN
- Subjects
- Adult, Female, Humans, Male, Young Adult, Body Weight, Therapeutic Equivalency, Triazoles pharmacokinetics, Tryptamines pharmacokinetics
- Abstract
Objective: Evaluation of the bioequivalence of the tested Relonova, tablets, 10 mg and Maxalt, tablets, 10 mg drugs on an empty stomach in healthy volunteers., Material and Methods: The pharmacokinetic analysis population included 40 volunteers, the safety analysis population included 40 volunteers. The average age of randomized volunteers (men - 20, women - 20) was 29.3±8.9 years, height 1.71±0.09 m, body weight 70.86±11.66 kg, mean BMI 24.18±2.81 kg/m
2 . The method used high performance liquid chromatography with tandem mass spectrometric detection. Statistical analysis of the obtained data was performed based on the assumption of a log-normal distribution of the parameters AUC0-72 and Cmax., Results: The ratio of geometric means for the key pharmacokinetic parameters (AUC0-t, AUC0-inf and Cmax) of rizatriptan is close to 90%, CI is within the acceptable range for bioequivalent drugs (80-125%). The intrasubject variability (CVintra) for rizatriptan was 23.74% (Cmax), 10.94% (AUC0-t). The average profiles of the pharmacokinetic curves of rizatriptan when taking the test and reference drugs have similar shapes. Relonova and reference Maxalt are bioequivalent., Conclusion: The results of the study make it possible to recommend Relonova for further clinical study and wide practical application.- Published
- 2023
- Full Text
- View/download PDF
38. Discovery of Novel Orally Bioavailable Triazoles with Potent and Broad-Spectrum Antifungal Activity In Vitro and In Vivo.
- Author
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Ni T, Xie F, Hao Y, Li L, Zhu S, Wu H, Chi X, Yan L, Jiang Y, and Zhang D
- Subjects
- Animals, Mice, Candida albicans drug effects, Fluconazole pharmacology, Microbial Sensitivity Tests, Administration, Oral, Biological Availability, Antifungal Agents administration & dosage, Antifungal Agents chemistry, Antifungal Agents pharmacokinetics, Triazoles administration & dosage, Triazoles chemistry, Triazoles pharmacokinetics
- Abstract
In our continuing efforts to discover novel triazoles with improved antifungal activity in vitro and in vivo, a series of 41 novel compounds containing 1,2,3-triazole side chains were designed and synthesized via a click reaction based on our previous work. Most of the compounds showed moderate to excellent broad-spectrum antifungal activity in vitro. Among them, the most promising compound 9A
16 displayed excellent antifungal and anti-drug-resistant fungal ability (MIC80 = 0.0156-8 μg/mL). In addition, compound 9A16 showed powerful in vivo efficacy on mice systematically infected with Candida albicans SC5314, Cryptococcus neoformans H99, fluconazole-resistant C. albicans 100, and Aspergillus fumigatus 7544. Moreover, compared to fluconazole, compound 9A16 showed better in vitro anti-biofilm activity and was more difficult to induce drug resistance in a 1 month induction of resistance assay in C. albicans . With favorable pharmacokinetics, an acceptable safety profile, and high potency in vitro and in vivo, compound 9A16 is currently under preclinical investigation.- Published
- 2022
- Full Text
- View/download PDF
39. Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults.
- Author
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Shimizu R, Sonoyama T, Fukuhara T, Kuwata A, Matsuo Y, and Kubota R
- Subjects
- Adult, Humans, Administration, Oral, Area Under Curve, Cytochrome P-450 CYP3A, Dose-Response Relationship, Drug, Double-Blind Method, Enzyme Inhibitors, Healthy Volunteers, Midazolam therapeutic use, Peptide Hydrolases, Protease Inhibitors, SARS-CoV-2, Triazoles pharmacokinetics, Triazoles therapeutic use, Antiviral Agents pharmacokinetics, Antiviral Agents therapeutic use, Indazoles pharmacokinetics, Indazoles therapeutic use, Triazines pharmacokinetics, Triazines therapeutic use, COVID-19 Drug Treatment
- Abstract
Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced C
max and delayed Tmax of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.- Published
- 2022
- Full Text
- View/download PDF
40. New Perspectives on Antimicrobial Agents: Isavuconazole.
- Author
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Lewis JS 2nd, Wiederhold NP, Hakki M, and Thompson GR 3rd
- Subjects
- Antifungal Agents pharmacokinetics, Antifungal Agents therapeutic use, Caspofungin therapeutic use, Fungi, Humans, Nitriles pharmacokinetics, Nitriles therapeutic use, Pyridines, Triazoles pharmacokinetics, Triazoles therapeutic use, Voriconazole pharmacology, Voriconazole therapeutic use, Candidiasis, Invasive drug therapy, Invasive Fungal Infections drug therapy
- Abstract
Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi. Its current FDA-approved indications include the management of invasive aspergillosis as well as mucormycosis, though the latter indication is supported by limited clinical data. Isavuconazole did not achieve noninferiority to caspofungin for the treatment of invasive candidiasis and therefore lacks an FDA-approved indication for this invasive disease. Significant advantages of isavuconazole, primarily over voriconazole but in some circumstances posaconazole as well, make it an appealing option for the management of complex patients with invasive fungal infections. These potential advantages include lack of QTc interval prolongation, more predictable pharmacokinetics, a less complicated drug interaction profile, and improved tolerability, particularly when compared to voriconazole. This review discusses these topics in addition to addressing the in vitro activity of the compound against a variety of fungi and provides insight into other distinguishing factors among isavuconazole, voriconazole, and posaconazole. The review concludes with an opinion section in which the authors provide the reader with a framework for the current role of isavuconazole in the antifungal armamentarium and where further data are required.
- Published
- 2022
- Full Text
- View/download PDF
41. The impact of extracorporeal membrane oxygenation on the exposure to isavuconazole: a plea for thorough pharmacokinetic evaluation.
- Author
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Mertens B, Wauters J, Debaveye Y, Van Regenmortel N, Degezelle K, Meersseman P, Hermans G, Vandenbriele C, Van Daele R, and Spriet I
- Subjects
- Humans, Nitriles, Pyridines therapeutic use, Triazoles pharmacokinetics, Triazoles therapeutic use, Extracorporeal Membrane Oxygenation
- Published
- 2022
- Full Text
- View/download PDF
42. Decreased isavuconazole trough concentrations in the treatment of invasive aspergillosis in an adult patient receiving extracorporeal membrane oxygenation support.
- Author
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Miller M, Kludjian G, Mohrien K, and Morita K
- Subjects
- Adult, Humans, Male, Middle Aged, Nitriles, Pyridines, Triazoles pharmacokinetics, Triazoles therapeutic use, Aspergillosis drug therapy, Extracorporeal Membrane Oxygenation, Invasive Fungal Infections drug therapy, Respiratory Insufficiency etiology
- Abstract
Purpose: We present the case of a 56-year-old man with stage IV sarcoidosis on veno-venous extracorporeal membrane oxygenation (VV-ECMO) support for the management of respiratory failure receiving treatment with isavuconazole for invasive aspergillosis., Summary: VV-ECMO is an increasingly utilized life support therapy for patients with cardiac and/or respiratory failure, but its impact on medication dosing is poorly understood. In our patient with invasive Aspergillus infection receiving VV-ECMO, because of difficulty achieving therapeutic serum concentrations of voriconazole, we administered isavuconazole 372 mg intravenously (IV) every 8 hours for 6 doses followed by 372 mg IV once daily. Isavuconazole has a favorable pharmacokinetic and safety profile compared to other azole antifungal agents, but its high protein binding and lipophilicity raise concerns about drug sequestration in the VV-ECMO circuit. To optimize the efficacy and safety of this treatment, the isavuconazole trough concentration was measured at days 5 and 17, at which time it was 1.7 and 0.7 μg/mL, respectively. The dose was subsequently increased to 744 mg IV once daily, and serum trough concentrations were measured 5 and 8 days after dose adjustment, corresponding to 3.7 and 2.9 μg/mL, respectively. To our knowledge, this is the third report to describe inadequate isavuconazole trough concentrations during VV-ECMO support when utilizing standard doses., Conclusion: In the case described here, standard-dose isavuconazole (372 mg every 8 hours for 6 doses followed by 372 mg daily) did not achieve target trough concentrations in a patient receiving concomitant ECMO support., (© American Society of Health-System Pharmacists 2022. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
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43. Filgotinib: A Clinical Pharmacology Review.
- Author
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Namour F, Anderson K, Nelson C, and Tasset C
- Subjects
- Humans, Pyridines pharmacokinetics, Triazoles pharmacokinetics, Arthritis, Rheumatoid drug therapy, Janus Kinase Inhibitors therapeutic use, Pharmacology, Clinical
- Abstract
Filgotinib (GS-6034, formerly GLPG0634; Jyseleca
® ) is an oral, preferential Janus kinase (JAK)-1 inhibitor. Preferential inhibition of JAK1 modulates a subset of proinflammatory cytokines within the JAK-signal transducer and activator of transcription pathway, which differ from those inhibited by JAK2 or JAK3. Filgotinib is absorbed extensively and rapidly after oral dosing and is metabolized by carboxylesterase isoform 2 to form its primary active metabolite, GS-829845. The primary metabolite has a similar JAK1 selectivity profile but reduced activity (by 10-fold) and increased systemic exposure (approximately 16- to 20-fold) compared with the parent compound. Both the parent and the metabolite demonstrate low binding to plasma proteins in humans (< 60%). Systemic exposures of filgotinib and its primary metabolite increase dose proportionally over a 50- to 200-mg once-daily dose range. Food does not affect the pharmacokinetics of filgotinib. Consistent with their terminal elimination half-lives (4.9-10.7 h for filgotinib and 19.6-27.3 h for the primary metabolite), steady state in plasma is reached by day 2 for filgotinib and day 4 for its metabolite. Filgotinib is mainly eliminated in the urine as the metabolite (> 80%). Intrinsic factors such as age, sex, race, mild renal impairment, and mild-to-moderate hepatic impairment have either no or minimal impact on the pharmacokinetics of filgotinib and its primary metabolite. Filgotinib has a low drug-drug interaction potential, without clinically significant interactions with commonly coadministered medications in patients with inflammatory diseases. Both filgotinib and its primary metabolite are substrates of P-glycoprotein (P-gp); however, coadministration with P-gp inhibitors and inducers does not affect filgotinib pharmacokinetics sufficiently to warrant dose adjustment. Neither filgotinib nor its primary metabolite affect the corrected QT interval (calculated using Fridericia's correction formula). Filgotinib is approved for the treatment of rheumatoid arthritis and ulcerative colitis in Europe, the UK, and Japan., (© 2022. The Author(s).)- Published
- 2022
- Full Text
- View/download PDF
44. Discovery of Novel Sphingosine-1-Phosphate-1 Receptor Agonists for the Treatment of Multiple Sclerosis.
- Author
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Park SJ, Yeon SK, Kim Y, Kim HJ, Kim S, Kim J, Choi JW, Kim B, Lee EH, Kim R, Seo SH, Lee J, Kim JW, Lee HY, Hwang H, Bahn YS, Cheong E, Park JH, and Park KD
- Subjects
- Animals, Dogs, Drug Design, Encephalomyelitis, Autoimmune, Experimental drug therapy, Heart Rate drug effects, Humans, Isoxazoles chemical synthesis, Isoxazoles pharmacokinetics, Isoxazoles pharmacology, Lymphocyte Count, Lymphocytes drug effects, Male, Mice, Rats, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles pharmacokinetics, Triazoles pharmacology, beta-Arrestins drug effects, Multiple Sclerosis drug therapy, Sphingosine-1-Phosphate Receptors antagonists & inhibitors
- Abstract
The sphingosine-1-phosphate-1 (S1P
1 ) receptor agonists have great potential for the treatment of multiple sclerosis (MS) because they can inhibit lymphocyte egress through receptor internalization. We designed and synthesized triazole and isoxazoline derivatives to discover a novel S1P1 agonist for MS treatment. Of the two scaffolds, the isoxazoline derivative was determined to have excellent in vitro efficacy and drug-like properties. Among them, compound 21l was found to have superior drug-like properties as well as excellent in vitro efficacies (EC50 = 7.03 nM in β-arrestin recruitment and EC50 = 11.8 nM in internalization). We also confirmed that 21l effectively inhibited lymphocyte egress in the peripheral lymphocyte count test and significantly improved the clinical score in the experimental autoimmune encephalitis MS mouse model.- Published
- 2022
- Full Text
- View/download PDF
45. Lipophilicity and Pharmacokinetic Properties of New Anticancer Dipyridothiazine with 1,2,3-Triazole Substituents.
- Author
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Morak-Młodawska B and Jeleń M
- Subjects
- Chromatography, Reverse-Phase, Chromatography, Thin Layer, Humans, Hydrophobic and Hydrophilic Interactions, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacokinetics, Triazoles chemistry, Triazoles pharmacokinetics
- Abstract
The lipophilicity parameters (log P
calcd , RM 0 and log PTLC ) of 10 new active anticancer dipirydothiazines with a 1,2,3-triazole ring were determined theoretically using computational methods and experimentally by reversed-phase TLC. Experimental lipophilicity was assessed using mobile phases (a mixture of TRIS buffer and acetone) using a linear correlation between the RM retention parameter and the volume of acetone. The RM 0 parameter was correlated with the specific hydrophobic surface b, revealing two congenerative subgroups: 1,2,3-triazole-1,6-diazaphenothiazines and 1,2,3-triazole-1,8-diazaphenothiazines hybrids. The RM 0 parameter was converted into the log PTLC lipophilicity parameter using a calibration curve. The investigated compounds appeared to be moderately lipophilic. Lipophilicity has been compared with molecular descriptors and ADME properties. The new derivatives followed Lipinski's, Ghose's and Veber's rules.- Published
- 2022
- Full Text
- View/download PDF
46. Design, Synthesis, and Biological Evaluation of Triazolone Derivatives as Potent PPARα/δ Dual Agonists for the Treatment of Nonalcoholic Steatohepatitis.
- Author
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Feng Z, Xiang J, Liu H, Li J, Xu X, Sun G, Zheng R, Zhang S, Liu J, Yang S, Xu Q, Wen X, Yuan H, Sun H, and Dai L
- Subjects
- Animals, Anti-Inflammatory Agents chemical synthesis, Anti-Inflammatory Agents metabolism, Anti-Inflammatory Agents pharmacokinetics, Carbon Tetrachloride, Drug Design, Inflammation drug therapy, Inflammation pathology, Liver drug effects, Liver pathology, Liver Cirrhosis chemically induced, Liver Cirrhosis drug therapy, Liver Cirrhosis pathology, Male, Mice, Inbred C57BL, Microsomes, Liver drug effects, Molecular Structure, Non-alcoholic Fatty Liver Disease pathology, PPAR alpha metabolism, PPAR delta metabolism, Rats, Sprague-Dawley, Structure-Activity Relationship, Triazoles chemical synthesis, Triazoles metabolism, Triazoles pharmacokinetics, Mice, Rats, Anti-Inflammatory Agents therapeutic use, Non-alcoholic Fatty Liver Disease drug therapy, PPAR alpha agonists, PPAR delta agonists, Triazoles therapeutic use
- Abstract
Peroxisome proliferator-activator receptors α/δ (PPARα/δ) are regarded as potential therapeutic targets for nonalcoholic steatohepatitis (NASH). However, PPARα/δ dual agonist GFT-505 exhibited poor anti-NASH effects in a phase III clinical trial, probably due to its weak PPARα/δ agonistic activity and poor metabolic stability. Other reported PPARα/δ dual agonists either exhibited limited potency or had unbalanced PPARα/δ agonistic activity. Herein, we report a series of novel triazolone derivatives as PPARα/δ dual agonists. Among them, compound H11 exhibited potent and well-balanced PPARα/δ agonistic activity (PPARα EC
50 = 7.0 nM; PPARδ EC50 = 8.4 nM) and a high selectivity over PPARγ (PPARγ EC50 = 1316.1 nM) in PPAR transactivation assays. The crystal structure of PPARδ in complex with H11 revealed a unique PPARδ-agonist interaction. H11 , which had excellent PK properties and a good safety profile, showed potent in vivo anti-NASH effects in preclinical models. Together, H11 holds a great promise for treating NASH or other inflammatory and fibrotic diseases.- Published
- 2022
- Full Text
- View/download PDF
47. Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy.
- Author
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Dilger AK, Pabbisetty KB, Corte JR, De Lucca I, Fang T, Yang W, Pinto DJP, Wang Y, Zhu Y, Mathur A, Li J, Hou X, Smith D, Sun D, Zhang H, Krishnananthan S, Wu DR, Myers JE Jr, Sheriff S, Rossi KA, Chacko S, Zheng JJ, Galella MA, Ziemba T, Dierks EA, Bozarth JM, Wu Y, Crain E, Wong PC, Luettgen JM, Wexler RR, and Ewing WR
- Subjects
- Animals, Mice, Rabbits, Administration, Oral, Macaca fascicularis, Molecular Structure, Pyrazoles administration & dosage, Pyrazoles chemical synthesis, Pyrazoles pharmacokinetics, Pyrazoles therapeutic use, Rats, Sprague-Dawley, Structure-Activity Relationship, Rats, Carotid Artery Thrombosis drug therapy, Factor XIa antagonists & inhibitors, Fibrinolytic Agents administration & dosage, Fibrinolytic Agents chemical synthesis, Fibrinolytic Agents pharmacokinetics, Fibrinolytic Agents therapeutic use, Pyrimidines administration & dosage, Pyrimidines chemical synthesis, Pyrimidines pharmacokinetics, Pyrimidines therapeutic use, Triazoles administration & dosage, Triazoles chemical synthesis, Triazoles pharmacokinetics, Triazoles therapeutic use
- Abstract
Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (Weitz, J. I., Chan, N. C. Arterioscler. Thromb. Vasc. Biol. 2019, 39 (1), 7-12). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2' moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian ( BMS-986177/JNJ-70033093 , 17 , FXIa K
i = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.- Published
- 2022
- Full Text
- View/download PDF
48. First-in-human study of milvexian, an oral, direct, small molecule factor XIa inhibitor.
- Author
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Perera V, Wang Z, Luettgen J, Li D, DeSouza M, Cerra M, and Seiffert D
- Subjects
- Administration, Oral, Adult, Dose-Response Relationship, Drug, Double-Blind Method, Female, Food-Drug Interactions, Humans, Male, Middle Aged, Partial Thromboplastin Time, Pyrimidines pharmacokinetics, Pyrimidines pharmacology, Triazoles pharmacokinetics, Triazoles pharmacology, Factor XIa drug effects, Pyrimidines administration & dosage, Triazoles administration & dosage
- Abstract
Milvexian (BMS-986177/JNJ-70033093) is a small molecule, active-site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two-part, double-blind, placebo-controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200- and 500-mg panels investigated the pharmacokinetic impact of a high-fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once- or twice-daily) or placebo for 14 days. All milvexian dosing regimens were safe and well-tolerated, with only mild treatment-emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half-life (T
1/2 ) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose-proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose-dependent fashion. In MAD panels, steady-state milvexian plasma concentration was reached within 3 and 6 dosing days with once- and twice-daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development., (© 2021 Bristol Myers Squibb. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)- Published
- 2022
- Full Text
- View/download PDF
49. Proof of Concept in Assignment of Within-Subject Variability During Virtual Bioequivalence Studies: Propagation of Intra-Subject Variation in Gastrointestinal Physiology Using Physiologically Based Pharmacokinetic Modeling.
- Author
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Bego M, Patel N, Cristofoletti R, and Rostami-Hodjegan A
- Subjects
- Adolescent, Adult, Biological Availability, Cross-Over Studies, Delayed-Action Preparations, Gastrointestinal Tract physiology, Humans, Male, Middle Aged, Proof of Concept Study, Therapeutic Equivalency, Triazoles pharmacokinetics, Young Adult, Models, Biological, Research Design, Triazoles administration & dosage
- Abstract
While the concept of 'Virtual Bioequivalence' (VBE) using a combination of modelling, in vitro tests and integration of pre-existing data on systems and drugs is growing from its infancy, building confidence on VBE outcomes requires demonstration of its ability not only in predicting formulation-dependent systemic exposure but also the expected degree of population variability. The concept of variation influencing the outcome of BE, despite being hidden with the cross-over nature of common BE studies, becomes evident when dealing with the acceptance criteria that consider the 90% confidence interval (CI) around the relative bioavailability. Hence, clinical studies comparing a reference product against itself may fail due to within-subject variations associated with the two occasions that the individual receives the same formulation. In this proof-of-concept study, we offer strategies to capture the most realistic predictions of CI around the pharmacokinetic parameters by propagating physiological variations through physiologically based pharmacokinetic modelling. The exercise indicates feasibility of the approach based on comparisons made between the simulated and observed WSV of pharmacokinetic parameters tested for a clinical bioequivalence case study. However, it also indicates that capturing WSV of a large array of physiological parameters using backward translation modelling from repeated BE studies of reference products would require a diverse set of drugs and formulations. The current case study of delayed-release formulation of posaconazole was able to declare certain combinations of WSV of physiological parameters as 'not plausible'. The eliminated sets of WSV values would be applicable to PBPK models of other drugs and formulations. Graphical Abstract., (© 2021. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
50. High-throughput simultaneousquantification offive azole anti-fungal agents and one active metabolite in human plasma using ultra-high-performance liquid chromatography coupled to tandem mass spectrometry.
- Author
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Tanaka R, Shiraiwa K, Takano K, Ogata M, Honda S, Yoshida N, Okuhiro K, Yoshida M, Narahara K, Kai M, Tatsuta R, and Itoh H
- Subjects
- Chromatography, High Pressure Liquid, Female, Humans, Male, Tandem Mass Spectrometry, Antifungal Agents administration & dosage, Antifungal Agents pharmacokinetics, Drug Monitoring, Hematologic Neoplasms blood, Hematologic Neoplasms drug therapy, Triazoles administration & dosage, Triazoles pharmacokinetics
- Abstract
Objectives: For patients with hematological malignancy, triazole antifungal agents such as fluconazole (FLCZ), itraconazole (ITCZ), voriconazole (VRCZ), posaconazole (PSCZ) and isavuconazole (ISCZ) are often used for prophylaxis of deep mycosis. Since these azoles exhibit large pharmacokinetic variability, dose adjustment by therapeutic drug monitoring is recommended for some azoles. This study aimed to develop and validate a novel method for simultaneous determination of plasma concentrations of FLCZ, ITCZ, VRCZ, PSCZ, ISCZ and ITCZ-OH, an active metabolite of ITCZ, using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS)., Design & Methods: A high-throughput solid-phase extraction method using 96-well MCX µElution Plate was selected as the pretreatment procedure., Results: The calibration curves for FLCZ, ITCZ, ITCZ-OH, VRCZ, PSCZ and ISCZ showed good linearity (back-calculation of calibrators: relative error ≤ 15% [LLOQ: ≤ 20%]) over wide ranges of 100-100000, 20-20000, 40-40000, 20-20000, 5-5000 and 50-50000 ng/mL, respectively. The validation results of all six drugs fulfilled the criteria of the guidance for bioanalytical method validation of the US Food and Drug Administration for within-batch and batch-to-batch precision and accuracy. The extraction recovery rates were good at ≥ 74.9%, and almost no matrix effects were found for all the drugs. The trough (10 h post-dose in 1 patient on PSCZ) drug concentrations in patients with hematologic malignancy who received oral FLCZ, ITCZ, VRCZ or PSCZ were quantified using the method developed. The measurements for all samples were within the ranges of the calibration curves, demonstrating the feasibility of clinical application of the novel method., Conclusions: We have succeeded in developing a novel high-throughput method using UHPLC-MS/MS for simultaneous quantification of plasma concentrations of FLCZ, ITCZ, ITCZ-OH, VRCZ, PSCZ and ISCZ., (Copyright © 2021 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
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