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Large pharmacokinetic (PK) variability of fluconazole has been reported in critically ill patients, but the implications for fluconazole dosing remain unclear. The objectives of this study were to evaluate the population PK of fluconazole and identify appropriate dosage regimens by simulations. This was a retrospective analysis of fluconazole PK data from patients hospitalized in critical care and infectious disease departments. Both parametric and nonparametric population approaches were used. Various loading and maintenance fluconazole doses were evaluated by simulations, with computation of the probabilities of PK/pharmacodynamic (PD) target attainment (PTA) and cumulative fractions of response (CFR) based on international and local minimum inhibitory concentration (MIC) distributions of Candida sp. Data from 36 critically ill patients and 16 non-critically ill patients were available for model building ( n = 202 concentrations). The final model adequately described the data, including the external data set (13 patients). After 24 h of therapy, 65% and 74% of patients had trough and area under the concentration-time curve values below the usual targets. Standard dosages were associated with low PTA for MIC >1 mg/L at 24 h. Higher loading doses administered two times daily improved PTA. CFR were >90% for C. albicans with standard dosages, while they were very low for C. glabrata , even with high dosages. Candida species and associated MIC distributions strongly influence fluconazole dosage requirements. Higher loading doses may be necessary for the achievement of PK/PD targets up to MIC breakpoints. The use of fluconazole for invasive C. glabrata infection should be discouraged because of poor PK/PD target attainment., Competing Interests: The authors declare no conflict of interest.

Background and Objectives: Finerenone, a novel selective non-steroidal mineralocorticoid receptor antagonist, has been indicated in chronic kidney disease associated with type 2 diabetes mellitus. Considering the potential complications of diabetes, finerenone can be co-administered with various drugs, including fluconazole, diltiazem, and ritonavir. Given that finerenone is a substrate of cytochrome P450 (CYP) 3A4, the concurrent administration of finerenone with CYP3A4 inhibitors (diltiazem or fluconazole or ritonavir) could potentially lead to drug interactions, which may cause adverse events such as hyperkalemia. No studies have investigated interactions between finerenone and diltiazem or fluconazole or ritonavir. Therefore, this study aims to investigate the pharmacokinetic interaction of finerenone with diltiazem or fluconazole or ritonavir and to evaluate the impact of fluconazole on the pharmacodynamics of finerenone., Methods: The pharmacokinetic study included four rat groups (n = 8 rats/group), including a control group (finerenone alone) and test groups (finerenone pretreated with diltiazem or fluconazole or ritonavir) using both non-compartment analysis (NCA) and population pharmacokinetic (pop-PK) modeling. The pop-PK model was developed using non-linear mixed-effects modeling in NONMEM ® (version 7.5.0). In the pharmacodynamic study, serum potassium (K + ) levels were measured to assess the effects of fluconazole on finerenone-induced hyperkalemia., Results: The NCA results indicated that the area under the plasma concentration-time curve (AUC) of finerenone increased by 1.86- and 1.95-fold when coadministered with fluconazole and ritonavir, respectively. In contrast, diltiazem did not affect the pharmacokinetics of finerenone. The pharmacokinetic profiles of finerenone were best described by a one-compartment disposition with first-order elimination and dual first-order absorption kinetics. The pop-PK modeling results demonstrated that the apparent clearance of finerenone decreased by 50.3% and 49.2% owing to the effects of fluconazole and ritonavir, respectively. Additionally, the slow absorption rate, which represents the absorption in the distal intestinal tract of finerenone, increased by 55.7% due to the effect of ritonavir. Simultaneously, a pharmacodynamic study revealed that finerenone in the presence of fluconazole caused a significant increase in K + levels compared with finerenone alone., Conclusions: Coadministration of finerenone with fluconazole or ritonavir increased finerenone exposure in rats. Additionally, the administration of finerenone in the presence of fluconazole resulted in elevated K + levels in rats. Further clinical studies are required to validate these findings., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The dosing of fluconazole for young infants remains empirical because of the limited pharmacokinetic (PK) data. We aimed to establish a population PK model and assess the systematic exposure-response of commonly used regimens of fluconazole in Chinese infants. We included infants with a postnatal age of less than 120 days and received intravenous fluconazole. Both scheduled and scavenged plasma samples were collected, and fluconzaole concentration was determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using Phoenix NLME, and then Monte Carlo simulation was conducted to predict the probability of target attainment (PTA) of empirically used regimens of both prophylactic and therapeutic purposes. Based on 304 plasma samples from 183 young infants, fluconazole concentration data was best described by a one-compartment model with first-order elimination. Gestational Age (GA), postnatal age (PNA), and body weight (BW) were included in the final model as CL = 0.02*(GA/214)2.77*(PNA/13)0.24*exp(nCL); V = 1.56*(BW/1435)0.90*exp(nV). Model validation revealed the final model had qualified stability and acceptable predictive properties. Monte Carlo simulation indicated that under the same minimum inhibitory concentration (MIC) value and administration regimen, PTA decreased with GA and PNA. The commonly used prophylactic regimens can meet the clinical need, while higher doses might be needed for treatment of invasive candidiasis. This population PK model of fluconazole discriminated the impact of GA and PNA on CL and BW on V. Dosing adjustment was needed according to the GA and PNA of infants to achieve targeted exposures., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Infections represent a major risk for critically ill neonatal and paediatric patients requiring extracorporeal life-saving support such as extracorporeal membrane oxygenation (ECMO) and/or continuous renal replacement therapies (CRRT). Patient outcomes rely on achieving target antimicrobial concentrations. In critically ill adults on extracorporeal support, suboptimal antimicrobial concentrations have been shown to be common. Our objective was to systematically review antimicrobial pharmacokinetic studies in critically ill term neonatal and paediatric patients receiving ECMO and/or CRRT and compare them to similar cohorts of patients not receiving ECMO or CRRT., Methods: Studies published between 1990 and 2022 were identified through systematic searches in PUBMED, Embase, Web of Science, Medline, Google Scholar and CINAHL. Studies were included which provided antimicrobial pharmacokinetic parameters (volume of distribution and clearance) in the neonatal and paediatric patients receiving ECMO and/or CRRT. Studies were excluded if no antimicrobial pharmacokinetic parameters were described or could be calculated., Results: Forty-four pharmacokinetic studies were identified describing 737 patients, with neonatal patients recruited in 70% of the ECMO studies and <1% of the CRRT studies. Of all the studies, 50% were case reports or case series. The pharmacokinetics were altered for gentamicin, daptomycin, ceftolozane, micafungin, voriconazole, cefepime, fluconazole, piperacillin, and vancomycin, although considerable patient variability was described., Conclusion: Significant gaps remain in our understanding of the pharmacokinetic alterations in neonatal and paediatric patients receiving ECMO and CRRT support., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Fungal infections pose a significant challenge in numerous developing nations and worldwide, necessitating urgent solutions. Oral administration of antifungal medications often leads to severe adverse reactions. Hence, employing topical delivery systems is preferred to ensure efficient dermal delivery of antifungal agents while minimizing side effects. Furthermore, the incorporation of penetration enhancers into nanocarriers loaded with antifungal agents has demonstrated enhanced efficacy in combating mycotic infections. Consequently, ultra-deformable penetration enhancer-containing vesicles (PEVs) were developed to explore this promising approach. In this study, Labrasol ® and Transcutol ® were used as penetration enhancers in formulating ultra-deformable PEVs containing the antifungal agent Fluconazole (FCZ). The PEVs underwent comprehensive characterization, including measurements of particle size (PS), charge, and entrapment efficiency (EE%). The results revealed that the size of tested PEVs ranged from 100 to 762 nm. All particles exhibited a negative charge, with a minimum zeta potential (ZP) of -38.26 mV, and an intermediate entrapment efficiency (EE%) that reached approximately 40%w/w. Ex-vivo studies demonstrated the ability of PEVs to deliver FCZ to the dermis while minimizing transdermal delivery. The selected formula was tested in-vivo using candidiasis -induced rat model and showed a superiority in its antifungal effect against Candida Albicans compared to the drug control. Stability studies were executed for the selected formula, and revealed good stability shown by the insignificant change in the PS, ZP& EE% over a six-month period.

Physiologically based pharmacokinetic (PBPK) models of entrectinib and its equipotent metabolite, M5, were established in healthy adult subjects and extrapolated to pediatric patients to predict increases in steady-state systemic exposure on co-administration of strong and moderate CYP3A4 inhibitors (itraconazole at 5 mg/kg, erythromycin at 7.5-12.5 mg/kg and fluconazole at 3-12 mg/kg, respectively). Adult model establishment involved the optimization of fraction metabolized by CYP3A4 (0.92 for entrectinib and 0.98 for M5) using data from an itraconazole DDI study. This model captured well the exposure changes of entrectinib and M5 seen in adults co-administered with the strong CYP3A4 inducer rifampicin. In pediatrics, reasonable prediction of entrectinib and M5 pharmacokinetics in ≧2 year olds was achieved when using the default models for physiological development and enzyme ontogenies. However, a two to threefold misprediction of entrectinib and M5 exposures was seen in <2 year olds which may be due to missing mechanistic understanding of gut physiology and/or protein binding in very young children. Model predictions for ≧2 year olds showed that entrectinib AUC(0-t) was increased by approximately sevenfold and five to threefold by strong and high-moderate and low-moderate CYP3A4 inhibitors, respectively. Based on these victim DDI predictions, dose adjustments for entrectinib when given concomitantly with strong and moderate CYP3A4 inhibitors in pediatric subjects were recommended. These simulations informed the approved entrectinib label without the need for additional clinical pharmacology studies., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics © 2024 American Society for Clinical Pharmacology and Therapeutics.)

Objectives: The Fluconazole pharmacokinetic-pharmacodynamic relationship was investigated in a few clinical settings and only limited studies regarding burned patients are available. Thus, the authors aimed to investigate fluconazole pharmacokinetics changes and its impact on antifungal therapy coverage against dose-dependent Candida spp. applying the PK/PD approach in critically ill severely burned patients., Methods: Fluconazole was administered as a one-hour intravenous infusion of 200 mg q12h. Doses were increased according to the coverage based on the PK/PD approach. Blood samples were collected at the end of the infusion (1 st hour), two hours after (3 rd hour), and before the next dose (12 th or 24 th hour). Serum concentrations were obtained by HPLC-UV. Pharmacokinetic parameters were estimated by noncompartmental analysis and compared with data described in healthy subjects. The effectiveness predictive index was based on the AUC ss 0-24h /MIC ratio, with a target above 25., Results: Every pharmacokinetic parameter was reduced throughout all three sets of the study. Compared to healthy subjects, the volume of distribution was decreased about 3‒7 times, biological half-life was 2‒3 times shorter and total body clearance was slightly altered but statistically significant. Both half-life and total body clearance were correlated to the volume of distribution. Consequently, an increase in fluconazole daily dose was necessary to improve empiric coverage., Conclusions: Fluconazole pharmacokinetics is altered in critically ill severely burned patients, mainly related to the volume of distribution. Doses higher than usual may be necessary to reach the PK/PD target and guarantee antifungal coverage against dose-dependent Candida spp. up to MIC 32 mg/L., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 HCFMUSP. Published by Elsevier España, S.L.U. All rights reserved.)

Candida species is one of the pathogenic fungi of the eye responsible for keratitis that frequently causes vision impairment and blindness. Effective treatment requires long-term use of antifungal drugs, which is opposed by the defensive mechanisms of the eye and inadequate corneal penetration. The objective of this study was to develop a carrier for prolonged ocular application of fluconazole (FLZ) to treat keratitis. FLZ was encapsulated into chitosan fibrous matrices (F1-F4) using different chitosan concentrations (0.02, 0.1, 0.5, and 1%w/v, respectively) by freeze-drying as a single-step technique. Studying the morphology and surface properties of the inserts revealed a porous matrix with fibrous features with a large surface area. Thermal stability and chemical compatibility were confirmed by DSC/TGA/DTA and FT-IR, respectively. Loading capacity (LC) and entrapment efficiency (EE) were determined. According to the in vitro release study, F4 (0.11 mg mg -1 LC and 87.53% EE) was selected as the optimum insert because it had the most sustained release, with 15.85% burst release followed by 75.62% release within 12 h. Ex vivo corneal permeation study revealed a 1.2-fold increase in FLZ permeation from F4 compared to FLZ aqueous solution. Also, in the in vivo pharmacokinetic study in rabbits, F4 increased the AUC 0-8 of FLZ by 9.3-fold and its concentration in aqueous humor was maintained above the MIC through the experimentation time. Studies on cytotoxicity (MTT assay) provide evidence for the safety and biocompatibility of F4. Therefore, the freeze-dried FLZ-loaded chitosan fibrous insert could be a promising candidate for treating ocular keratitis., (© 2024. The Author(s).)

Introduction: Ibrexafungerp is a new triterpenoid antifungal agent with activity against a variety of fungal species, including Aspergillus spp. and echinocandin-resistant Candida spp., Areas Covered: This evaluation will summarize currently available clinical evidence on the use of ibrexafungerp in the treatment/prevention of vulvovaginal candidiasis (VVC) and detail the mechanism of action, pharmacokinetic/pharmacodynamic parameters, and ongoing/latest research involving ibrexafungerp., Expert Opinion: The evidence involving the utilization of ibrexafungerp for the treatment of VVC shows that it is superior when compared to placebo and has comparable clinical cure rates when compared with fluconazole. Ibrexafungerp demonstrates reliable coverage against several Candida spp. including echinocandin-resistant strains, Candida auris , and Aspergillus spp. For VVC, a dose of 300 mg (two 150 mg tablets) twice daily is recommended and does not require dose adjustments based on renal or hepatic function. The use of ibrexafungerp outside of VVC is currently under study with several ongoing trials showing promising interim data.

Background: Invasive fungal infections (IFIs) are severe and difficult-to-treat infections affecting immunocompromised patients. Antifungal drug penetration at the site of infection is critical for outcome and may be difficult to achieve. Data about antifungal drug distribution in infected human tissues under real circumstances of IFI are scarce., Methods: Multiple samples were obtained from soft tissue abscesses of a lung transplant patient with Candida albicans invasive candidiasis who underwent recurrent procedures of drainage, while receiving different consecutive courses of antifungal therapy [itraconazole (ITC), fluconazole, caspofungin]. Antifungal drug concentrations were measured simultaneously at the site of infection (surrounding inflammatory tissue and fluid content of the abscess) and in plasma for calculation of the tissue/plasma ratio (R). The concentration within the infected tissue was interpreted as appropriate if it was equal or superior to the MIC of the causal pathogen., Results: A total of 30 tissue samples were collected for measurements of ITC (n = 12), fluconazole (n = 17) and caspofungin (n = 1). Variable concentrations were observed in the surrounding tissue of the lesions with median R of 2.79 (range 0.51-15.9) for ITC and 0.94 (0.21-1.37) for fluconazole. Concentrations ranges within the fluid content of the abscesses were 0.39-1.83 for ITC, 0.66-1.02 for fluconazole and 0.23 (single value) for caspofungin. The pharmacodynamic target (tissue concentration ≥ MIC) was achieved in all samples for all three antifungal drugs., Conclusions: This unique dataset of antifungal drug penetration in infected human soft tissue abscesses suggests that ITC, fluconazole and caspofungin could achieve appropriate concentrations in soft tissue abscesses., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy., Methods: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed., Results: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted., Conclusions: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment., Competing Interests: C.W. received speaker fees from OrganOx Ltd and was an advisory board member for Jazz Pharmaceuticals and Nefro Health. A.B. holds a share of a patent in connection with the OrganOx metra. The other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Fluconazole (FLZ) has been widely used in the treatment of infection caused by Candida albicans, including the treatment of vulvovaginal candidiasis (VVC). However, when delivered orally, FLZ faces numerous limitations due to its poor solubility and undergoes the symptoms of first-pass metabolism. In this study, we developed the combinatorial approach of nanocrystals (NCs) and dissolving microneedles (DMNs) for effective local vaginal delivery of FLZ. The formulation containing 1.0% w/v PVA as stabilizer with 12 h of milling time process was found to be an optimal combination to fabricate FLZ as NCs (FLZ-NCs) with optimum size particle and PDI value (less than 0.25). Furthermore, the in vitro release study also showed a superior percentage of FLZ release up to 89.51 ± 7.52%. In combination with the DMNs, the FLZ recovery was 96.45 ± 2.38% with the insertion percentage in average of 76.14 ± 2.28% and height decreased percentage was only 7.53 ± 0.56%. Moreover, the ex vivo investigation and anti-candidiasis activity of DMNs-FLZ-NCs in vaginal model showed better results compared to other conventional preparations, such as film patch and hydrogel containing FLZ., (© 2023. Controlled Release Society.)

Fluconazole (FNL) is one of the first-line treatments for fungal keratitis as it is an effective broad-spectrum antimicrobial commonly administered orally or topically. However, FNL has a very low water solubility, limiting its drug formulation, therapeutic application, and bioavailability through tissues. To overcome these limitations, this study aimed to develop FNL inclusion complexes (FNL-IC) with cyclodextrin (α-cyclodextrin, sulfobutylether-β-cyclodextrin, and hydroxypropyl-γ cyclodextrin) and incorporate it into a dissolvable microneedle (DMN) system to improve solubility and drug penetration. FNL-IC was evaluated for saturation solubility, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, minimum inhibitory concentration, minimum fungicidal concentration, and time-killing assay. DMN-FNL-IC was evaluated for mechanical and insertion properties, surface pH, moisture absorption ability, water vapor transmission, and drug content recovery. Moreover, ocular kinetic, ex vivo antimicrobial, in vivo antifungal, and chorioallantoic membrane (HET-CAM) assays were conducted to assess the overall performance of the formulation. Mechanical strength and insertion properties revealed that DMN-FNL-IC has great mechanical and insertion properties. The in vitro release of FNL-IC was significantly improved, exhibiting a 9-fold increase compared to pure FNL. The ex vivo antifungal activity showed significant inhibition of Candida albicans from 6.54 to 0.73 log cfu/mL or 100-0.94%. In vivo numbers of colonies of 0.87 ± 0.13 log cfu/mL (F2), 4.76 ± 0.26 log cfu/mL (FNL eye drops), 3.89 ± 0.24 log cfu/mL (FNL ointments), and 8.04 ± 0.58 log cfu/mL (control) showed the effectiveness of DMN preparations against other standard commercial preparations. The HET-CAM assay showed that DMN-FNL-IC (F2) did not show any vascular damage. Finally, a combination of FNL-IC and DMN was developed appropriately for ocular delivery of FNL, which was safe and increased the effectiveness of treatments for fungal keratitis.

Fluconazole (FZ) is a potential antifungal compound for treating superficial and systemic candidiasis. However, the use of conventional oral drug products has some limitations. The development of buccal film may be a potential alternative to oral formulations for FZ delivery. The present study involved the development of novel FZ-loaded solid lipid nanoparticles (FZ-SLNs) in pectin solutions and the investigation of their particle characteristics. The particle sizes of the obtained FZ-SLNs were in the nanoscale range. To produce pectin films with FZ-SLNs, four formulations were selected based on the small particle size of FZ-SLNs and their suitable polydispersity index. The mean particle sizes of all chosen FZ-SLNs formulations did not exceed 131.7 nm, and the mean polydispersity index of each formulation was less than 0.5. The properties of films containing FZ-SLNs were then assessed. The preparation of all FZ-SLN-loaded pectin films provided the mucoadhesive matrices. The evaluation of mechanical properties unveiled the influence of particle size variation in FZ-SLNs on the integrity of the film. The Fourier-transform infrared spectra indicated that hydrogen bonds could potentially form between the pectin-based matrix and the constituents of FZ-SLNs. The differential scanning calorimetry thermogram of each pectin film with FZ-SLNs revealed that the formulation was thermally stable and behaved in a solid state at 37 °C. According to a drug release study, a sustained drug release pattern with a burst in the initial stage for all films may be advantageous for reducing the lag period of drug release. All prepared films with FZ-SLNs provided a sustained release of FZ over 6 h. The films containing FZ-SLNs with a small particle size provided good permeability across the porcine mucosa. All film samples demonstrated antifungal properties. These results suggest the potential utility of pectin films incorporating FZ-SLNs for buccal administration.

Warfarin is a widely used anticoagulant, and its S-enantiomer has higher potency compared to the R-enantiomer. S-warfarin is mainly metabolized by cytochrome P450 (CYP) 2C9, and its pharmacological target is vitamin K epoxide reductase complex subunit 1 (VKORC1). Both CYP2C9 and VKORC1 have genetic polymorphisms, leading to large variations in the pharmacokinetics (PKs) and pharmacodynamics (PDs) of warfarin in the population. This makes dosage management of warfarin difficult, especially in the case of drug-drug interactions (DDIs). This study provides a whole-body physiologically-based pharmacokinetic/PD (PBPK/PD) model of S-warfarin for predicting the effects of drug-drug-gene interactions on S-warfarin PKs and PDs. The PBPK/PD model of S-warfarin was developed in PK-Sim and MoBi. Drug-dependent parameters were obtained from the literature or optimized. Of the 34 S-warfarin plasma concentration-time profiles used, 96% predicted plasma concentrations within twofold range compared to observed data. For S-warfarin plasma concentration-time profiles with CYP2C9 genotype, 364 of 386 predicted plasma concentration values (~94%) fell within the twofold of the observed values. This model was tested in DDI predictions with fluconazole as CYP2C9 perpetrators, with all predicted DDI area under the plasma concentration-time curve to the last measurable timepoint (AUC last ) ratio within twofold of the observed values. The anticoagulant effect of S-warfarin was described using an indirect response model, with all predicted international normalized ratio (INR) within twofold of the observed values. This model also incorporates a dose-adjustment method that can be used for dose adjustment and predict INR when warfarin is used in combination with CYP2C9 perpetrators., (© 2024 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This multicenter study describes the population pharmacokinetics (PK) of fluconazole in critically ill patients receiving concomitant extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) and includes an evaluation of different fluconazole dosing regimens for achievement of target exposure associated with maximal efficacy. Serial blood samples were obtained from critically ill patients on ECMO and CRRT receiving fluconazole. Total fluconazole concentrations were measured in plasma using a validated chromatographic assay. A population PK model was developed and Monte Carlo dosing simulations were performed using Pmetrics in R. The probability of target attainment (PTA) of various dosing regimens to achieve fluconazole area under the curve to minimal inhibitory concentration ratio (AUC 0-24 /MIC) >100 was estimated. Eight critically ill patients receiving concomitant ECMO and CRRT were included. A two-compartment model including total body weight as a covariate on clearance adequately described the data. The mean (±standard deviation, SD) clearance and volume of distribution were 2.87 ± 0.63 L/h and 15.90 ± 13.29 L, respectively. Dosing simulations showed that current guidelines (initial loading dose of 12 mg/kg then 6 mg/kg q24h) achieved >90% of PTA for a MIC up to 1 mg/L. None of the tested dosing regimens achieved 90% of PTA for MIC above 2 mg/L. Current fluconazole dosing regimen guidelines achieved >90% PTA only for Candida species with MIC <1 mg/L and thus should be only used for Candida-documented infections in critically ill patients receiving concomitant ECMO and CRRT. Total body weight should be considered for fluconazole dose., Competing Interests: The authors declare no conflict of interest.

Background: Tirabrutinib is an orally effective, approved, and highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor for the treatment of recurrent or refractory primary central nervous system lymphoma (PCNSL)., Objective: This study aimed to develop an ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) method for the determination of tirabrutinib concentration in rat plasma, where zanubrutinib was used as an internal standard (IS). This method was also applied to study whether tirabrutinib would interact with voriconazole, itraconazole, and fluconazole in rats, providing a reference value for clinical medication guidance., Methods: In the current study, the organic solvent protein precipitation method was used to treat plasma samples, which is simple and reproducible. Tirabrutinib (m/z 455.32 → 320.21) and zanubrutinib ( m/z 472.13 → 455.04) were separated on a Waters Acquity BEH C18 column (2.1 × 50 mm, 1.7 μm) and detected by multiple reaction monitoring (MRM) in positive ionization mode., Results: The method showed good linearity in the range of 5-3000 ng/mL for tirabrutinib with the lower limit of quantification (LLOQ) of 5 ng/mL. The recovery and matrix effects were 85.7-91.0% and 102.0-113.3%, respectively. The accuracy, precision, stability, and carry-over effect were also acceptable. The method could also be used for determining the pharmacokinetic interaction of tirabrutinib in rats. The results showed AUC 0→∞ of tirabrutinib to be increased by 139.3% and 83.9% in the presence of voriconazole and fluconazole, respectively, while itraconazole had little effect., Conclusion: It is necessary to monitor the concentration of tirabrutinib in patients when it is combined with voriconazole and fluconazole to achieve a better therapeutic effect and reduce the risk of adverse reaction. Further research should be conducted in the future., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

This was an open-label, randomized study in healthy Chinese participants to assess the bioequivalence of 2 fluconazole 150-mg capsules under fasted and fed conditions. The study consisted of 2 treatment periods, separated by a 14-day washout period. Thirty-six participants were enrolled, with 18 participants each in the fasted and fed groups. In each treatment period, participants received a single oral dose of the test or reference fluconazole 150-mg capsule. After washout, participants received the alternate treatment. Blood samples for pharmacokinetic analysis were collected from 1 hour before dosing to 72 hours after dosing. The median plasma concentration-time profiles were similar for both treatments under fasted and fed conditions. Bioequivalence of fluconazole between the 2 capsules was demonstrated as 90% confidence intervals of the geometric mean ratios for the maximum plasma concentration and area under the plasma concentration-time curve from time 0 to 72 hours after dosing under fasted and fed conditions were within the acceptable range of 80%-125%. Overall, 7 participants reported at least 1 treatment-emergent adverse event; all were mild in severity. No serious adverse events or deaths were reported. The test fluconazole capsule was bioequivalent to the reference capsule, and a single dose was well tolerated. Clinicaltrials.gov ID: NCT03621072., (© 2023 Pfizer. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Objectives: This study aims at evaluating fluconazole exposure in critically ill patients and identifying variables associated with the latter., Patients and Methods: This was a 2-year (2018-2019) retrospective multicenter cohort study. Adult patients > 18 years-old with at least one fluconazole concentration measurement during their ICU stay were included., Results: Twenty patients were included. Only 11 patients had a fluconazole trough concentration (Cmin) within the target range (≥15 mg/L). According to bivariable analysis, SOFA score, GGT, fluconazole clearance, Ke, and Vd, were independently associated with a decrease in fluconazole Cmin. The median loading dose required to achieve the Cmin target appeared to be greater in patients with higher SOFA or GGT level and in patients undergoing renal replacement therapy., Conclusions: This study supports recommendation for routine fluconazole therapeutic drug monitoring in ICU patients so as to avoid underexposure, especially if SOFA score is ≥ 7 and/or GGT is ≥ 100 U/L., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Fluconazole can be effective in the treatment of superficial mycoses in dogs. However, the pharmacokinetics of fluconazole have not yet been evaluated to determine its optimal dosing regimen., Objectives: This study aimed to determine the plasma concentration of fluconazole after single and multiple administrations at two different dosages in dogs., Methods and Materials: Eight healthy beagle dogs were divided into two groups, and each group received either 5 or 10 mg/kg of fluconazole per os. The pharmacokinetics of fluconazole was determined following single and multiple administrations p.o. Single- and multiple-dose treatment periods were separated by a washout period of seven days. Plasma concentrations of fluconazole were determined by established high-performance liquid chromatography coupled with tandem mass spectrometry system., Results: In the 5 mg/kg group, the mean maximum concentrations (C max ) and the area under the plasma concentrations (AUC 0-24h ) were 4.84 μg/mL and 85.56 μg*h/mL, respectively, after single administration and 6.58 μg/mL and 119.52 μg*h/mL, respectively, after multiple administrations. In the 10 mg/kg group, the C max and AUC 0-24h were 5.67 μg/mL and 109.19 μg*h/mL, respectively, after single administration and 15.10 μg/mL and 291.51 μg*h/mL, respectively, after multiple administrations. The C max (p < 0.001) and AUC 0-24h (p < 0.001) were significantly lower in the 5 mg/kg group than those in the 10 mg/kg group at multiple administrations., Conclusions and Clinical Relevance: Fluconazole accumulates in plasma and exhibits dose-proportional pharmacokinetics after multiple doses, and was safe and well tolerated at these doses for short-term administration., (© 2022 ESVD and ACVD.)

Purpose: Fedratinib is an orally administered Janus kinase (JAK) 2-selective inhibitor for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. In vitro, fedratinib is predominantly metabolized by cytochrome P450 (CYP) 3A4 and to a lesser extent by CYP2C19. Coadministration of fedratinib with CYP3A4 inhibitors is predicted to increase systemic exposure to fedratinib. This study evaluated the effect of multiple doses of the dual CYP3A4 and CYP2C19 inhibitor, fluconazole, on the pharmacokinetics of a single dose of fedratinib., Methods: In this non-randomized, fixed-sequence, open-label study, healthy adult participants first received a single oral dose of fedratinib 100 mg on day 1. Participants then received fluconazole 400 mg on day 10 and fluconazole 200 mg once daily on days 11-23, with a single oral dose of fedratinib 100 mg on day 18. Pharmacokinetic parameters were calculated for fedratinib administered with and without fluconazole., Results: A total of 16 participants completed the study and were included in the pharmacokinetic population. Coadministration of fedratinib with fluconazole increased maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUC 0-t ) of fedratinib by 21% and 56%, respectively, compared with fedratinib alone. Single oral doses of fedratinib 100 mg administered with or without fluconazole were well tolerated., Conclusions: Systemic exposure after a single oral dose of fedratinib was increased by up to 56% when fedratinib was coadministered with fluconazole compared with fedratinib alone., Trial Registry: CLINICALTRIALS.GOV: NCT04702464., (© 2022. The Author(s).)

Background: Fluconazole is commonly used to treat or prevent fungal infections. It is typically used orally but in critical situations, IV administration is needed. Obesity may influence the pharmacokinetics and therapeutic efficacy of a drug. In this study, we aim to assess the impact of obesity on fluconazole pharmacokinetics given orally or IV to guide dose adjustments for the obese population., Methods: We performed a prospective pharmacokinetic study with intensive sampling in obese subjects undergoing bariatric surgery (n = 17, BMI ≥ 35 kg/m2) and non-obese healthy controls (n = 8, 18.5 ≤ BMI < 30.0 kg/m2). Participants received a semi-simultaneous oral dose of 400 mg fluconazole capsules, followed after 2 h by 400 mg IV. Population pharmacokinetic modelling and simulation were performed using NONMEM 7.3., Results: A total of 421 fluconazole concentrations in 25 participants (total bodyweight 61.0-174 kg) until 48 h after dosing were obtained. An estimated bioavailability of 87.5% was found for both obese and non-obese subjects, with a 95% distribution interval of 43.9%-98.4%. With increasing total bodyweight, both higher CL and Vd were found. Sex also significantly impacted Vd, being 27% larger in male compared with female participants., Conclusions: In our population of obese but otherwise healthy individuals, obesity clearly alters the pharmacokinetics of fluconazole, which puts severely obese adults, particularly if male, at risk of suboptimal exposure, for which adjusted doses are proposed., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A prospective single-center study was conducted to characterize the pharmacokinetics (PK) of fluconazole (FLCZ) in extremely low-birth-weight infants (ELBWIs) who received fosfluconazole (F-FLCZ). Intravenous F-FLCZ was administered at a dose of 3 mg/kg of body weight every 72 h during the first 2 weeks of life, every 48 h during the third and fourth weeks of life, and every 24 h after 5 weeks of life. Blood samples from ELBWIs treated with F-FLCZ were collected using scavenged samples. The concentration of FLCZ was determined using liquid chromatography-tandem mass spectrometry. The population pharmacokinetic model was established using Phenix NLME 8.2 software. In total, 18 ELBWIs were included in this analysis. Individual PK parameters were determined by a one-compartment analysis with first-order conversion. Postmenstrual age (PMA), serum creatinine (SCr), and alkaline phosphatase were considered covariates for clearance (CL). The mean population CL and the volume of distribution were 0.011 L/h/kg 0.75 and 0.95 L/kg, respectively. Simulation assessments with the final model revealed that the current regimen (3 mg/kg every 72 h) could achieve the proposed target FLCZ trough concentration (>2 μg/mL) in 43.3% and 72.2% of infants with a PMA of ≥37 and 30 to 36 weeks, respectively, and an SCr level of <0.5 mg/dL. Shortened dosing intervals (every 48 or 24 h) might improve the probability of target attainment. This study was the first to assess the PK of F-FLCZ in ELBWI, as well as the first to provide fundamental information about FLCZ exposure after F-FLCZ administration, with the goal of facilitating dose optimization in the ELBWI population. IMPORTANCE Invasive fungal infection is an important cause of mortality and morbidity in very preterm or very-low-birth-weight infants. In order to limit the risk of invasive fungal infections in this population, the administration of fluconazole is generally recommended for extremely low-birth-weight infants admitted to a neonatal intensive care unit with a Candida species colonization prevalence rate of >10%, under the guidelines of the Infectious Diseases Society of America. Fosfluconazole can reduce the volume of solution required for intravenous therapy compared to fluconazole because it has increased solubility, which is a major advantage for infants undergoing strict fluid management. To date, no study has demonstrated the fluconazole pharmacokinetics after fosfluconazole administration in neonates and infants, and this needs to be clarified. Here, we characterized the pharmacokinetics of fluconazole in extremely low-birth-weight infants who received F-FLCZ and explored the appropriate dosage in this patient population.

Introduction: Fluconazole is an important antifungal in the prevention and treatment of invasive Candida infections in neonates, even though its use in preterm infants is still off-label. Here, we performed a population pharmacokinetic study on fluconazole in preterm neonates in order to optimise dosing through the identified predictive patient characteristics., Methods: Fluconazole concentrations obtained from preterm infants from two studies were pooled and analysed using NONMEM V.7.3. The developed model was used to evaluate current dosing practice. A therapeutic dosing strategy aiming to reach a minimum target exposure of 400 and 200 mg×hour/L per 24 hours for fluconazole-susceptible C. albicans meningitis and other systemic infections, respectively, was developed., Results: In 41 preterm neonates with median (range) gestational age 25.3 (24.0-35.1) weeks and median postnatal age (PNA) at treatment initiation 1.4 (0.2-32.5) days, 146 plasma samples were collected. A one-compartment model described the data best, with an estimated clearance of 0.0147 L/hour for a typical infant of 0.87 kg with a serum creatinine concentration of 60 µmol/L and volume of distribution of 0.844 L. Clearance was found to increase with 16% per 100 g increase in actual body weight, and to decrease with 12% per 10 µmol/L increase in creatinine concentration once PNA was above 1 week. Dose adjustments based on serum creatinine and daily dosing are required for therapeutic target attainment., Conclusion: In preterm neonates, fluconazole clearance is best predicted by actual body weight and serum creatinine concentration. Therefore, fluconazole dosing should not only be based on body weight but also on creatinine concentration to achieve optimal exposure in all infants., Ethics Statement: The Erasmus MC ethics review board approved the protocol of the DINO Study (MEC-2014-067) and the Radboud UMC ethics review board waived the need for informed consent for cohort 2 (CMO-2021-8302). Written informed consent from parents/legal guardians was obtained prior to study initiation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Fuzuloparib (AiRuiYi TM , formerly fluzoparib, SHR3162) is a new orally active poly adenosine diphosphate ribose polymerase (PARP) inhibitor. It has multiple pharmacological activities in breast, ovarian, and prostatic cancer. Fuzuloparib is mainly metabolized through the enzyme CYP3A4 may slow fuzuloparib metabolism and increase its concentrations in blood. We evaluated the pharmacokinetics and tolerability of fuzuloparib by fluconazole, which is a broad antifungal agent and a moderate inhibitor of CYP3A4., Methods: In this study, the effects of CYP3A4 inhibition on the pharmacokinetics of fuzuloparib were assessed in a total of 20 healthy Chinese male subjects in an open-label, two-period, single-sequence, crossover study., Results: Pharmacokinetic parameters, including the maximal plasma concentration (C max ) , the plasma concentration-time curve from time 0 to last measurable area under concentration (AUC 0-t ), and from time 0 to infinity (AUC 0-∞ ), were increased by 32.4%, 104.5%, and 109.6%, with corresponding 90% confidence intervals of (23-43%), (93-116%), and (98-122%), respectively, when fluconazole was combined with fuzuloparib compared to fuzuloparib alone. There was also a slight increase in the incidence of treatment emergent adverse events, including hyperlipidemia and elevated aspartate transaminase., Conclusion: The fuzuloparib is 150 mg b.i.d in clinics use. Our results suggest that fuzuloparib could well be tolerated when administered as a single 20 mg oral dose alone or co-administered with 400 mg fluconazole in healthy male subjects. It is recommended to avoid using moderate CYP3A4 inhibitors together with fuzuloparib or instead of 50 mg when necessary., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A simple, cost-effective and sensitive liquid chromatography-based bio-analytical method has been developed and validated for therapeutic drug monitoring of fluconazole (FLUC) in human serum. Integration of online mixed-mode solid-phase extraction (SPE) into the analytical system was the key for direct injection of untreated serum samples. A short protein-coated (PC) µBondapak CN silica column (PC-µB-CN-column) as a SPE tool and phosphate buffer saline (PBS) (pH 7.4) as an eluent were applied in the extraction step. PC-µB-CN-column operates in two different chromatographic modes. Using PBS, proteins were extracted from serum samples by size-exclusion liquid chromatography, while FLUC trapping was reversed-phase liquid chromatography dependent. FLUC was then eluted from the PC-µB-CN-column onto the quantification position using a mixture of acetonitrile-distilled deionized water (20:80, v/v) as an eluent and ODS analytical column. FLUC was separated at ambient temperature (22 ± 1 °C) and detected at 260 nm. The method was linear over the range of 200-10000 ng/mL. FLUC recovery in untreated serum samples ranged from 97.8 to 98.8% and showed good accuracy and precision. The reliability of the developed method was evaluated by studying the pharmacokinetic profile of FLUC in humans after an oral administration of a single 150 mg tablet., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Extracorporeal membrane oxygenation (ECMO) can affect antimicrobial pharmacokinetics. This case report describes a 33-year-old male with newly diagnosed acquired immunodeficiency syndrome presenting in acute severe type 1 respiratory failure. On investigation, the patient had positive cultures for Candida albicans from respiratory specimens and high blood cytomegalovirus titres, and required venovenous ECMO therapy for refractory respiratory failure. Intravenous fluconazole (6 mg/kg, 24-h) and ganciclovir (5 mg/kg, 12-h) was commenced. Pre-oxygenator, post-oxygenator and arterial blood samples were collected after antibiotic administration, and were analysed for total fluconazole and ganciclovir concentrations. Although there was a 40% increase in the volume of distribution for fluconazole relative to healthy volunteers, the pharmacodynamic targets for prophylaxis were still met. The area under the curve exposure of ganciclovir (50.78 mg•h/L) achieved target thresholds. The ECMO circuit had no appreciable effect on achievement of therapeutic exposures of fluconazole and ganciclovir., Competing Interests: Declaration of Competing Interest None declared., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

The present study describes a special lipid-polyethylene glycol matrix solid lipid nanoparticles (SLNs; 138 nm; -2.07 mV) for ocular delivery. Success of this matrix to encapsulate (entrapment efficiency - 62.09%) a hydrophilic drug, fluconazole (FCZ-SLNs), with no burst release (67% release in 24 h) usually observed with most water-soluble drugs, is described presently. The system showed 164.64% higher flux than the marketed drops (Zocon ® ) through porcine cornea. Encapsulation within SLNs and slow release did not compromise efficacy of FCZ-SLNs. Latter showed in vitro and in vivo antifungal effects, including antibiofilm effects comparable to free FCZ solution. Developed system was safe and stable (even to sterilisation by autoclaving); and showed optimal viscosity, refractive index and osmotic pressure. These SLNs could reach up to retina following application as drops. The mechanism of transport via corneal and non-corneal transcellular pathways is described by fluorescent and TEM images of mice eye cross sections. Particles streamed through the vitreous, crossed inner limiting membrane and reached the outer retinal layers.

Letermovir is a prophylactic agent for cytomegalovirus infection and disease in adult cytomegalovirus-seropositive recipients of allogeneic hematopoietic stem cell transplant. As the antifungal agent fluconazole is administered frequently in transplant recipients, a drug-drug interaction study was conducted between oral letermovir and oral fluconazole. A phase 1 open-label, fixed-sequence study was performed in healthy females (N = 14, 19-55 years). In Period 1, a single dose of fluconazole 400 mg was administered. Following a 14-day washout, a single dose of letermovir 480 mg was administered (Period 2), and after a 7-day washout, single doses of fluconazole 400 mg and letermovir 480 mg were coadministered in Period 3. Pharmacokinetics and safety were evaluated. The pharmacokinetics of fluconazole and letermovir were not meaningfully changed following coadministration. Fluconazole geometric mean ratio (GMR; 90% confidence interval [CI]) with letermovir for area under the concentration-versus-time curve from time 0 to infinity (AUC 0-∞ ) was 1.03 (0.99-1.08); maximum concentration (C max ) was 0.95 (0.92-0.99). Letermovir AUC 0-∞ GMR (90%CI) was 1.11 (1.01-1.23), and C max was 1.06 (0.93-1.21) following coadministration with fluconazole. Coadministration of fluconazole and letermovir was generally well tolerated., (© 2020, The American College of Clinical Pharmacology.)

Physiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (K I ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUC ss,0-24 ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUC ss,0-24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Oral antidyslipidaemic drug pemafibrate is cleared from human plasma via hepatic uptake by organic anion transporting polypeptide (OATP) 1B1 and oxidation by cytochromes P450 (P450) 2C8, 2C9 and 3A4. The pharmacokinetic profiles of pemafibrate with virtual administrations of P450 inhibitors and/or disease interactions were generated using a physiologically based pharmacokinetic (PBPK) model previously established for co-administration of pemafibrate with OATP1B1 inhibitors. This PBPK model was validated in the current study using reported maximum pemafibrate plasma concentrations and areas under the curve from interaction studies in healthy subjects co-administered with clopidogrel (P450 2C8 inhibitor), fluconazole (P450 2C9/3A4 inhibitor) or clarithromycin (P450 3A4 inhibitor). Virtual co-administrations of pemafibrate with clopidogrel, fluconazole or clarithromycin increased the predicted plasma exposures of pemafibrate 1.4-1.7-fold, 1.2-1.4-fold and 2.9-11-fold, respectively, in subjects with or without moderate or severe renal impairment or Child-Pugh A or B liver cirrhosis. Some of the exposure-enhancing effects of clarithromycin may originate from its inhibitory potential toward OATP1B1, because the estimated effects of itraconazole (a P450 3A4 inhibitor) were only minor. Simulations using the current PBPK model in groups of virtual subjects with or without renal or hepatic impairment revealed modified pharmacokinetic profiles for pemafibrate following co-administration of typical P450 inhibitors.

Purpose: Develop a physiologically based pharmacokinetic (PBPK) model of ivosidenib using in vitro and clinical PK data from healthy participants (HPs), refine it with clinical data on ivosidenib co-administered with itraconazole, and develop a model for patients with acute myeloid leukemia (AML) and apply it to predict ivosidenib drug-drug interactions (DDI)., Methods: An HP PBPK model was developed in Simcyp Population-Based Simulator (version 15.1), with the CYP3A4 component refined based on a clinical DDI study. A separate model accounting for the reduced apparent oral clearance in patients with AML was used to assess the DDI potential of ivosidenib as the victim of CYP3A perpetrators., Results: For a single 250 mg ivosidenib dose, the HP model predicted geometric mean ratios of 2.14 (plasma area under concentration-time curve, to infinity [AUC 0-∞ ]) and 1.04 (maximum plasma concentration [C max ]) with the strong CYP3A4 inhibitor, itraconazole, within 1.26-fold of the observed values (2.69 and 1.0, respectively). The AML model reasonably predicted the observed ivosidenib concentration-time profiles across all dose levels in patients. Predicted ivosidenib geometric mean steady-state AUC 0-∞ and C max ratios were 3.23 and 2.26 with ketoconazole, and 1.90 and 1.52 with fluconazole, respectively. Co-administration of the strong CYP3A4 inducer, rifampin, predicted a greater DDI effect on a single dose of ivosidenib than on multiple doses (AUC ratios 0.35 and 0.67, C max ratios 0.91 and 0.81, respectively)., Conclusion: Potentially clinically relevant DDI effects with CYP3A4 inducers and moderate and strong inhibitors co-administered with ivosidenib were predicted. Considering the challenges of conducting clinical DDI studies in patients, this PBPK approach is valuable in ivosidenib DDI risk assessment and management.

This multi-institutional study was designed to determine the clinical pharmacokinetics of fluconazole and outcomes in client-owned dogs (n = 37) and cats (n = 35) with fungal disease. Fluconazole serum concentrations were measured. Pharmacokinetic analysis was limited to animals at steady state (≥72 hr of treatment). The mean (range) body weight in 31 dogs was 25.6 (2.8-58.2) kg and in 31 cats was 3.9 (2.4-6.1) kg included in pharmacokinetic analyses. The dose, average steady-state serum concentrations (C SS ), and oral clearance in dogs were 14.2 (4.5-21.3) mg/kg/d, 26.8 (3.8-61.5) µg/mL, and 0.63 ml min -1  kg -1 , respectively, and in cats were 18.6 (8.2-40.0) mg/kg/d, 32.1 (1.9-103.5) µg/mL, and 0.61 ml min -1  kg -1 , respectively. Random inter-animal pharmacokinetic variability was high in both species. Two dogs had near twofold increases in serum fluconazole when generic formulations were changed, suggesting lack of bioequivalence. Median C SS for dogs and cats achieving clinical remission was 19.4 and 35.8 µg/ml, respectively. Starting oral doses of 10 mg/kg q12h in dogs and 50-100 mg total daily dose in cats are recommended to achieve median C SS associated with clinical remission. Due to the large pharmacokinetic variability, individualized dose adjustments based on C SS (therapeutic drug monitoring) and treatment failure should be considered., (© 2020 John Wiley & Sons Ltd.)

Background: The goal of therapeutic drug monitoring (TDM) is to determine the appropriate exposure of difficult-to-manage medications to optimize the clinical outcomes in patients in various clinical situations. Concerning antifungal treatment, and knowing that this procedure is expensive and time-consuming, TDM is particularly recommended for certain systemic antifungals: i.e., agents with a well-defined exposure-response relationship and unpredictable pharmacokinetic profile or narrow therapeutic index. Little evidence supports the routine use of TDM for polyenes (amphotericin B), echinocandins, fluconazole or new azoles such as isavuconazole, despite the fact that a better understanding of antifungal exposure may lead to a better response., Aims: The aim of this work is to review published pharmacokinetic/pharmacodynamic data on systemically administered antifungals, focusing on those for which monitoring is not routinely recommended by experts., Sources: A MEDLINE search of the literature in English was performed introducing the following search terms: amphotericin B, fluconazole, itraconazole, voriconazole, posaconazole, triazoles, caspofungin, micafungin, anidulafungin, echinocandins, pharmacokinetics, pharmacodynamics, and therapeutic drug monitoring. Review articles and guidelines were also screened., Content: This review collects different pharmacokinetic/pharmacodynamic aspects of systemic antifungals and summarizes recent threshold values for clinical outcomes and adverse events. Although for polyenes, echinocandins, fluconazole and isavuconazole extensive clinical validation is still required for a clear threshold and a routine monitoring recommendation, particular points such as liposome structure or complex pathophysiological conditions affecting final exposure are discussed. For the rest, their better-defined exposure-response/toxicity relationships allow access to useful threshold values and to justify routine monitoring. Additionally, clinical data are needed to better define thresholds that can minimize the development of antifungal resistance., Implications: General TDM for all systemic antifungals is not recommended; however, this approach may help to establish an adequate antifungal exposure for a favourable response, prevention of toxicity or development of resistance in special clinical circumstances., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: We sought to compare meropenem and fluconazole dosing in the neonatal intensive care unit with recommendations based on published pharmacokinetic (PK) studies in infants., Methods: We performed an observational cohort study of infants <90 days postnatal age who received a course of meropenem or fluconazole who were treated in neonatal intensive care units managed by the Pediatrix Medical Group (1997-2016). We defined any dose amount from 80% to 120% of the published recommendation to constitute an appropriate dose of either antimicrobial. We calculated the percentage of appropriately dosed courses overall and by discharge year. We then evaluated the change in appropriate dosing over time using a nonparametric test of trend to evaluate the proportion of appropriately dosed courses of each antimicrobial by discharge year., Results: A total of 3608 infants were administered 2025 courses of meropenem and 1201 courses of fluconazole. Of all meropenem courses, 32% were dosed appropriately (increased significantly over time; P = 0.01), while 17% of fluconazole courses were dosed appropriately (increased significantly over time; P = 0.01). Median dosing for both meropenem and fluconazole was at or below recommendations; therefore, under-dosing was more common., Conclusions: There was marked discordance between actual fluconazole and meropenem dosing and dosing recommendation in PK publications, yet adherence to PK-based doses showed improvement over time.

The aim of this perspective is to give an overlook on the utility of pharmacokinetics/pharmacodynamics (PK/PD) in predicting the efficacy of antifungals in invasive candidiasis. Overall, from the available literature it appears that bridging data of PK/PD of antifungals from the laboratory to the clinic for the treatment of invasive candidiasis are feasible only partially. Fluconazole is the only antifungal agent having the pharmacodynamic threshold of efficacy identified in experimental animal models convincingly validated in the clinical setting of invasive candidiasis as well. Conversely, for voriconazole and posaconazole data on this topic are very limited. For the echinocandins, robust PK/PD identified in the laboratory represented the rationale for defining differential clinical breakpoints of echinocandins against different species of Candida by the regulatory agencies. However, translation of the findings in the clinical setting provided conflicting results. Data on PK/PD of amphotericin B and flucytosine in models of invasive candidiasis are quite limited, and clinical studies assessing the role of drug exposure on efficacy are currently lacking. The expectation is that prospective studies could test more and more frequently the validity of experimental PK/PD data of antifungals in the clinical setting of invasive candidiasis. The findings could represent a step forward in addressing adequate antifungal stewardship programmes., (© 2020 Blackwell Verlag GmbH.)

Aim: The aim of this study was to build and verify a preliminary physiologically based pharmacokinetic (PBPK) model of Chinese pregnant women. The model was used to predict maternal pharmacokinetics (PK) of 6 predominantly renally cleared drugs., Method: Based on SimCYP Caucasian pregnancy population dataset, the preliminary Chinese pregnant population was built by updating several key parameters and equations according to physiological parameters of Chinese (or Japanese) pregnant women. Drug-specific parameters of 6 renally cleared drugs were validated through PBPK modeling of Caucasian non-pregnant, Caucasian pregnant and Chinese non-pregnant population. The preliminary PBPK model of Chinese pregnant population was then developed by integrating the preliminary Chinese pregnant population and the drug-specific parameters. This model was verified by comparing the predicted maternal PK of these 6 drugs with the observed in vivo data from the literature., Results: The preliminary Chinese pregnant population PBPK model successfully predicted the PK of 6 target drugs for different pregnancy stages. The predicted plasma concentrations time profiles fitted the observed data well, and most predicted PK parameters were within 2-fold of observed data., Conclusions: The preliminary Chinese pregnant population PBPK model provided a useful tool to predict the maternal PK of 6 predominantly renally cleared drugs in Chinese pregnant women., (© 2020 John Wiley & Sons, Ltd.)

Background: Gilteritinib, a novel, potent FLT3/AXL inhibitor, was recently approved in Japan and USA for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with a FLT3 mutation., Purpose and Methods: In this study, we aimed to develop and validate a sensitive and simple ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantification of gilteritinib in plasma and to investigate whether CYP3A4 inhibitors (fluconazole and itraconazole) could influence the pharmacokinetics of gilteritinib from a drug-drug interaction study in rats. Sample preparation was done by a simple protein crash with acetonitrile containing the internal standard (IS) pirfenidone, followed by UPLC-MS/MS quantification., Results: The assay was successfully validated in a 1-500 ng/mL calibration range for gilteritinib, where the lower limit of quantification (LLOQ) was set at 1 ng/mL. The intra-day and inter-day precisions for gilteritinib were less than 10.6%, and the accuracies were in the range of -14.5% to 11.1%. Recovery and matrix effect of the analyte and IS were acceptable, and the analyte was stable during the assay and storage in plasma samples. The validated UPLC-MS/MS method was successfully applied to a drug-drug interaction study between gilteritinib and CYP3A4 inhibitors (fluconazole and itraconazole) in rats. Itraconazole significantly increased the exposure of gilteritinib, and affected the pharmacokinetics of gilteritinib in rats, not fluconazole., Conclusion: A further clinical study should be conducted to investigate the effect of itraconazole on the metabolism of gilteritinib in subjects., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Wang et al.)

Aims: To characterize the population pharmacokinetics (PK) of sildenafil and its active metabolite, N-desmethyl sildenafil (DMS), in premature infants., Methods: We performed a multicentre, open-label trial to characterize the PK of sildenafil in infants ≤28 weeks gestation and < 365 postnatal days (cohort 1) or < 32 weeks gestation and 3-42 postnatal days (cohort 2). In cohort 1, we obtained PK samples from infants receiving sildenafil as ordered per the local standard of care (intravenous [IV] or enteral). In cohort 2, we administered a single IV dose of sildenafil and performed PK sampling. We performed a population PK analysis and dose-exposure simulations using the software NONMEM®., Results: We enrolled 34 infants (cohort 1 n = 25; cohort 2 n = 9) and collected 109 plasma PK samples. Sildenafil was given enterally (0.42-2.09 mg/kg) in 24 infants in cohort 1 and via IV (0.125 or 0.25 mg/kg) in all infants in cohort 2. A 2-compartment PK model for sildenafil and 1-compartment model for DMS, with presystemic conversion of sildenafil to DMS, characterized the data well. Coadministration of fluconazole (n = 4), a CYP3A inhibitor, resulted in an estimated 59% decrease in sildenafil clearance. IV doses of 0.125, 0.5 and 1 mg/kg every 8 hours (in the absence of fluconazole) resulted in steady-state maximum sildenafil concentrations that were generally within the range of those reported to inhibit phosphodiesterase type 5 activity in vitro., Conclusions: We successfully characterized the PK of sildenafil and DMS in premature infants and applied the model to inform dosing for a follow-up, phase II study., (© 2019 The British Pharmacological Society.)

Objective: To evaluate drug interactions between fluconazole and the intravenous (IV) anesthetic induction agents, ketamine and midazolam., Study Design: Randomized parallel study., Animals: A group of 12 adult healthy Beagle dogs., Methods: Dogs were randomly allocated to two groups of six dogs. Dogs in group KM were administered IV ketamine (7 mg kg -1 ) and IV midazolam (0.25 mg kg -1 ), and dogs in group KMF were administered fluconazole (5 mg kg -1 ) orally 12 and 24 hours prior to ketamine-midazolam using the same doses as KM. Sedation scores (0-4) were assigned by investigators unaware of group assignment. Heart rate (HR) and times to sternal and standing were obtained and compared between groups for differences with p < 0.05 considered statistically significant. Blood was obtained and plasma drug concentrations were measured using liquid chromatography-mass spectrometry., Results: The times to sternal, mean 32.3 and 24.6 minutes, for groups KMF and KM, respectively, were not different between the groups. The time to standing, 73 and 36 minutes in groups KMF and KM, respectively, was significantly different (p = 0.002). The duration of elevated HR compared with baseline was longer in KMF (110 minutes) than in KM (25 minutes) (p < 0.05). In group KMF, one dog developed hyperthermia (40.6 °C), which resolved spontaneously. The clearance of ketamine and midazolam was significantly slower (approximately 50%) and the area under the curves were significantly higher (two-fold) in group KMF (p = 0.02)., Conclusions and Clinical Relevance: A significant interaction between oral fluconazole and IV ketamine-midazolam occurred, but the effects appear minor in healthy dogs. Based on these data, a single dose of ketamine-midazolam is not contraindicated in dogs treated with fluconazole, but the duration of effects and pharmacokinetics are altered., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the safety and efficacy of two dosing regimens of oral ibrexafungerp (formerly SCY-078), a novel orally bioavailable β-glucan synthase inhibitor, in subjects with invasive candidiasis versus the standard of care (SOC) and to identify the dose to achieve target exposure (15.4 μM·h) in >80% of the intended population., Methods: In a multinational, open-label study, patients with documented invasive candidiasis were randomized to receive step-down therapy to one of three treatment arms: two dosing regimens of novel oral ibrexafungerp or the SOC treatment following initial echinocandin therapy. Plasma samples were collected to evaluate exposure by population pharmacokinetic (PK) modelling. Safety was assessed throughout the study and global response at the end of treatment., Results: Out of 27 subjects enrolled, 7 received ibrexafungerp 500 mg, 7 received ibrexafungerp 750 mg and 8 received the SOC. Five did not meet criteria for randomization. Population PK analysis indicated that an ibrexafungerp 750 mg regimen is predicted to achieve the target exposure in ∼85% of the population. The rate of adverse events was similar among patients receiving ibrexafungerp or fluconazole. Similar favourable response rates were reported among all groups: 86% (n = 6) in the ibrexafungerp 750 mg versus 71% (n = 5) in both the fluconazole and ibrexafungerp 500 mg treatment arms. The one subject treated with continued micafungin had a favourable global response., Conclusions: The oral ibrexafungerp dose estimated to achieve the target exposure in subjects with invasive candidiasis is 750 mg daily. This dose was well tolerated and achieved a favourable global response rate, similar to the SOC., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Ruxolitinib is metabolized by cytochrome P450 (CYP)3A4 and CYP2C9. Dual inhibitors of these enzymes (like fluconazole) lead to increased ruxolitinib exposure relative to a single pathway inhibition of CYP3A4 or CYP2C9. The magnitude of this interaction, previously assessed via physiologically based pharmacokinetic (PBPK) models, was confirmed in an open-label, phase 1 study in healthy subjects., Methods: The effect of multiple doses (200 mg) of fluconazole on single-dose (10 mg) PK of ruxolitinib was investigated including evaluation of the safety and tolerability. The PK parameters of ruxolitinib alone (reference) were compared to those of ruxolitinib combined with fluconazole (test). The point estimate and corresponding two-sided 90% confidence interval for the difference between means of test and reference parameters were determined., Results: All enrolled subjects (N = 15) completed the study. When coadministered with fluconazole, geometric means of ruxolitinib PK parameters C max , AUC last , and AUC inf increased by 47%, 234%, and 232%, respectively, vs ruxolitinib alone. The median T max decreased slightly, apparent clearance decreased approximately threefold, and elimination half-life increased approximately 2.5-fold, upon ruxolitinib administration with fluconazole vs ruxolitinib alone. These results were consistent with the prospective predictions from a SimCYP PBPK model. Adverse events (AEs) were reported in six subjects (none were suspected to be related to ruxolitinib); no death or on-treatment serious AE was reported., Conclusions: Coadministration of ruxolitinib with fluconazole significantly increased ruxolitinib systemic exposure; however, no AEs were attributed to ruxolitinib. Concomitant use of ruxolitinib with fluconazole (dose ≤ 200 mg) may require dose reduction/modification of ruxolitinib.

Aims: Quizartinib is an oral, highly potent and selective next-generation FMS-like tyrosine kinase 3 (FLT3) inhibitor under investigation in patients with FLT3-internal tandem duplication-mutated acute myeloid leukaemia. This drug-drug interaction study assessed the pharmacokinetics (PK) of quizartinib when coadministered with strong or moderate cytochrome P450 3A (CYP3A) inhibitors., Methods: In this parallel-group study, subjects were randomised to receive: (i) quizartinib + ketoconazole; (ii) quizartinib + fluconazole; or (iii) quizartinib alone. On Days 1-28, subjects received ketoconazole 200 mg or fluconazole 200 mg twice daily, and on Day 8, all subjects received a single 30-mg quizartinib dose. Blood samples were collected for PK analyses, steady-state PK parameters were simulated by superpositioning, and safety was assessed., Results: Ninety-three healthy subjects were randomised; 86 completed the study. When administered with ketoconazole, geometric mean ratios (90% confidence interval) for quizartinib maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) from time 0 extrapolated to infinity were 117% (105%, 130%) and 194% (169%, 223%), respectively, vs quizartinib alone. Steady-state PK simulation demonstrated ~2-fold increase of both steady-state C max and AUC from time 0 to the end of the dosing interval when quizartinib was administered with ketoconazole due to accumulation of quizartinib at steady state. When administered with fluconazole, geometric mean ratios (90% confidence interval) for quizartinib C max and AUC from time 0 extrapolated to infinity were 111% (100%, 124%) and 120% (104%, 138%), respectively, vs quizartinib alone. Overall, 5.4% of subjects experienced quizartinib-related adverse events; no serious adverse events or deaths occurred., Conclusions: These results suggest reducing the dose of quizartinib when coadministered with a strong CYP3A inhibitor, but not with a moderate or weak CYP3A inhibitor. This dose reduction was implemented in phase 3 evaluation of quizartinib., (© 2019 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: To determine the effects of fluconazole on oral methadone pharmacokinetics and central effects mediated by opioid receptors in dogs., Study Design: Prospective, incomplete block., Animals: A total of 12 healthy Beagle dogs., Methods: Dogs were randomly allocated into two groups of six dogs. In total, four treatments (two treatments/group) were administered including: oral methadone (1 mg kg -1 ); oral fluconazole (5 mg kg -1 ) every 12 hours starting 24 hours prior to oral methadone (1 mg kg -1 ); oral fluconazole (2.5 mg kg -1 ) every 12 hours starting 24 hours prior to oral methadone (1 mg kg -1 ); and oral fluconazole (5 mg kg -1 ) every 24 hours starting 12 hours prior to oral methadone (1 mg kg -1 ). At least 28 days were implemented as a washout period between fluconazole treatments. Rectal temperature (RT), heart rate (HR), respiratory rate (f R ), sedation scores and blood samples were obtained for 24 hours after methadone administration. Plasma drug concentrations were measured with liquid chromatography/mass spectrometry., Results: Significantly higher maximum plasma methadone concentration (mean, 25-46 ng mL -1 ) occurred in all fluconazole-administered treatments than in methadone alone (1.5 ng mL -1 ). The mean 12 hour methadone plasma concentration in fluconazole treatments was 11-20 ng mL -1 . Significantly decreased RT and variable sedation occurred in all fluconazole treatments, but no changes occurred with methadone alone. There were no differences in HR or f R among treatments., Conclusions and Clinical Relevance: Fluconazole significantly increases the extent and duration of oral methadone exposure in dogs resulting in significant central opioid effects., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24-50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24-33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children., (© 2019 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

Fluconazole is an antifungal agent with reported evidence for its prophylactic effect against systemic fungal infection in preterm infants. The aim of this study was to build a population pharmacokinetic model to evaluate the pharmacokinetic characteristics of intravenous and oral fluconazole in preterm infants with the current prophylactic fluconazole dosing regimen. A pharmacokinetic model was developed using 301 fluconazole concentrations from 75 preterm infants with a baseline body weight (WT) ranging from 0.5 to 1.5 kg and an estimated glomerular filtration rate (eGFR) ranging from 12.9 to 58.5 ml/min/1.73 m 2 Eligible infants received an intravenous or oral dose of 3 mg/kg of body weight of fluconazole, twice weekly with a ≥72-h dose interval, for 4 weeks. The model was qualified with basic goodness-of-fit diagnostics, visual predictive checks, and bootstrapping. The fluconazole pharmacokinetics was well described with a one-compartment linear model with a proportional residual error. The population clearance (CL) and volume of distribution ( V ) were derived as 0.0197 × (WT/1.00) 0.746 × (eGFR/25.0) 0.463 × exp(η) and 1.04 × WT × exp(η), respectively. Such covariate analyses augment the awareness of the need for personalized dosing in preterm infants. (This study has been registered at ClinicalTrials.gov under identifier NCT01683760)., (Copyright © 2019 American Society for Microbiology.)

Tamoxifen is an antiestrogen drug that is widely used in the adjuvant chemotherapy of estrogen receptor-α (ERα)-positive breast cancer. Chemotherapy could suppress immune function in breast cancer patients, which may cause invasive fungal infections (IFIs). Triazoles (voriconazole, fluconazole, and itraconazole) were commonly used for IFI. The physiologically based pharmacokinetic (PBPK) models were developed to investigate the influence of different triazoles on tamoxifen pharmacokinetics in this paper. To investigate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on tamoxifen pharmacokinetics. Adjusted physicochemical data and pharmacokinetic parameters of voriconazole, fluconazole, itraconazole, and tamoxifen were obtained from published literatures. PBPK models were built and verified in healthy subjects using GastroPlus™. Voriconazole, itraconazole, and tamoxifen were administered orally. Fluconazole was administered intravenously. Simulated plasma concentration-time curves of the voriconazole, fluconazole, itraconazole, and tamoxifen showed good agreement with the observed profiles, respectively. The DDI simulations showed that the pharmacokinetic parameters of tamoxifen were increased by various degrees when coadministered with different triazoles. In healthy subjects, the area under the plasma concentration-time curve from 0 to t h (AUC 0-t ) of tamoxifen was increased by 41%, 5%, and1% when coadministrated with voriconazole, fluconazole, and itraconazole, respectively. The PBPK models adequately characterized the pharmacokinetics of tamoxifen and triazoles. Among the three triazoles, voriconazole exhibited the greatest effect on tamoxifen pharmacokinetics. In clinical practice, an effective dosage adjustment of tamoxifen may need to be considered and TDM for tamoxifen is advisable to guide dosing and optimize therapy when coadministered with voriconazole.

Fungal keratitis may cause vision loss if it is not treated. Methods other than ocular delivery exhibited several limitations. No previous studies investigated and compared ocular bioavailability of fluconazole (FLZ) from niosomal gels and microemulsions. Niosomal gels of FLZ (0.3% w/w) based on Span ® 60 and cholesterol (CH) using 1% w/w carbopol ® 934 (CP) were evaluated. FLZ microemulsions (0.3% w/v) containing isopropyl myristate (IPM, as oil phase) and a 3:1 mixture of Tween ® 80 (as surfactant) and polyethylene glycol 400 (PEG 400, as cosurfactant) were characterized. Optimized formulations were compared for their ocular bioavailability in rabbit's. Nanoscopic niosomes (63.67-117.13 nm) and microemulsions (57.05-59.93 nm) showed respective negative zeta potential ranges of -45.37 to -61.40 and -20.50 to -31.90 mV and sustained release up to 12 h. Entrapment efficiency (EE%) of niosomes ranged from 56.48% to 70.67%. Niosomal gels were more sustainable than niosomes and microemulsions. The most stable niosomal gel based on Span ® 60 and CH at a molar ratio of 5:5 and microemulsion containing 45% w/w IPM and 40% w/w of 3:1 Tween ® 80-PEG 400 mixture significantly (p < 0.0001) enhanced FLZ ocular bioavailability compared with its solution. Niosomal gel showed higher bioavailability than microemulsion by ≈2-fold.

The objective of the study was to determine the therapeutic equivalence evaluated through in vitro studies of four brands of drugs containing amoxicillin, doxycycline, and fluconazole purchased at pharmaceutical facilities in Metropolitan Lima, and to establish their interchangeability with a reference product (RP). A validated method of visible ultraviolet spectrophotometry was used to determine the dissolution profile. The similarity factor (f2) was used to establish the therapeutic equivalence, being considered equivalent if the values of f2 were between 50 and 100. For doxycycline, the four drugs were equivalent in vitro to the RP; for amoxicillin, only two drugs were equivalent in vitro to the RP; and for fluconazole, none was equivalent in vitro to the RP. It is concluded that some amoxicillin and fluconazole drugs circulating in the national market do not meet the therapeutic equivalence assessed by in vitro studies; in other words, they are not interchangeable.

The purpose of this review is to critically analyze published data evaluating the impact of azole pharmacokinetic and pharmacodynamic parameters, MICs, and Candida species on clinical outcomes in patients with candidemia. Clinical breakpoints (CBPs) for fluconazole and voriconazole, which are used to determine susceptibility, have been defined by the Clinical and Laboratory Standards Institute (CLSI) for Candida species. Studies evaluating the relationship between treatment efficacy and in vitro susceptibility, as well as the pharmacodynamic targets, have been conducted in patients treated with fluconazole for candidemia; however, for species other than Candida albicans and Candida glabrata , and for other forms of invasive candidiasis, data remain limited and randomized trials are not available. Limited data evaluating these relationships with voriconazole are available. While pharmacodynamic targets for posaconazole and isavuconazole have been proposed based upon studies conducted in murine models, CBPs have not been established by CLSI. Fluconazole remains an important antifungal agent for the treatment of candidemia, and data supporting its use based on in vitro susceptibility are growing, particularly for C. albicans and C. glabrata Further investigation is needed to establish the roles of voriconazole, posaconazole, and isavuconazole in the treatment of candidemia and for all agents in the treatment of other forms of invasive candidiasis., (Copyright © 2018 American Society for Microbiology.)