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INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) infections are a serious threat to public health. Vancomycin (VAN) remains the primary treatment for these infections, and achieving the recommended area under the curve (AUC) target has been linked to improved clinical outcomes. The current VAN therapeutic monitoring guidelines recommend a loading dose (LD) of 20-35 mg/kg to rapidly attain targeted VAN exposures within 24 h of therapy. However, there is a paucity of data describing the impact of VAN LD on day 1 area under the curve (AUC0-24). This study aims to employ pharmacokinetic (PK) equations to calculate and describe the AUC0-24 following a VAN LD of 20 mg/kg. METHODS: This was a retrospective study of adult patients who were loaded with VAN 20 mg/kg, received ≥ 48 h of treatment, and had two consecutive serum VAN levels collected within 24 h. Linear, non-trapezoidal PK equations and two post-infusion VAN levels were used to calculate AUC0-24. Therapeutic AUC0-24 was defined as 400-600 mg/l*h. RESULTS: Among 123 included patients, the median age was 46 years (IQR 36, 62), 54% (67/123) of the patients had a body mass index (BMI) ≥ 30 kg/m2 and 27% (33/123) were admitted to the intensive care unit (ICU). Following a LD of 20 mg/kg, 50% (61/123) of the patients met the therapeutic AUC0-24, while 22% (27/123) of the patients were subtherapeutic, and 28% (35/123) were supratherapeutic. Compared with patients who achieved therapeutic AUC0-24, patients with subtherapeutic AUC0-24 were more likely to be younger (44 vs. 37 years old) and have a BMI ≥ 30 kg/m2 (67 vs. 52%). In contrast, patients with supratherapeutic AUC0-24 were more likely to be older (64 vs. 44 years old) and to have chronic kidney disease diagnosis (23 vs. 7%) when compared to patients who achieved a therapeutic AUC0-24. CONCLUSIONS: Only 50% of patients achieve the target AUC0-24 following a VAN 20 mg/kg LD, with younger, heavier patients underexposed and older patients with renal impairment overexposed, suggesting that different dosing strategies are needed for these populations.

BACKGROUND: Primaquine (PQ) is the prototype 8-aminoquinoline drug, a class which targets gametocytes and hypnozoites. The World Health Organization (WHO) recommends adding a single low dose of primaquine to the standard artemisinin-based combination therapy (ACT) in order to block malaria transmission in regions with low malaria transmission. However, the haemolytic toxicity is a major adverse outcome of primaquine in glucose-6-phosphate dehydrogenase (G6PD)-deficient subjects. This study aimed to characterize the pharmacokinetic properties of primaquine and its major metabolites in G6PD-deficient subjects. METHODS: A single low-dose of primaquine (0.4-0.5 mg/kg) was administered in twenty-eight African males. Venous and capillary plasma were sampled up to 24 h after the drug administration. Haemoglobin levels were observed up to 28 days after drug administration. Only PQ, carboxy-primaquine (CPQ), and primaquine carbamoyl-glucuronide (PQCG) were present in plasma samples and measured using liquid chromatography mass spectrometry. Drug and metabolites pharmacokinetic properties were investigated using nonlinear mixed-effects modelling. RESULTS: Population pharmacokinetic properties of PQ, CPQ, and PQCG can be described by one-compartment disposition kinetics with a transit-absorption model. Body weight was implemented as an allometric function on the clearance and volume parameters for all compounds. None of the covariates significantly affected the pharmacokinetic parameters. No significant correlations were detected between the exposures of the measured compounds and the change in haemoglobin or methaemoglobin levels. There was no significant haemoglobin drop in the G6PD-deficient patients after administration of a single low dose of PQ. CONCLUSIONS: A single low-dose of PQ was haematologically safe in this population of G6PD-normal and G6PD-deficient African males without malaria. Trial registration NCT02535767.

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

BackgroundEach year 25 000-32 000 children develop rifampicin- or multidrug-resistant tuberculosis (RR/MDR-TB), and many more require preventive treatment. Levofloxacin is a key component of RR/MDR-TB treatment and prevention, but the existing pharmacokinetic data in children have not yet been comprehensively summarized. We aimed to characterize levofloxacin pharmacokinetics through an individual patient data meta-analysis of available studies and to determine optimal dosing in children.MethodsLevofloxacin concentration and demographic data were pooled from 5 studies and analyzed using nonlinear mixed effects modeling. Simulations were performed using current World Health Organization (WHO)-recommended and model-informed optimized doses. Optimal levofloxacin doses were identified to target median adult area under the time-concentration curve (AUC)24 of 101 mg·h/L given current standard adult doses.ResultsData from 242 children (2.8 years [0.2-16.8] was used). Apparent clearance was 3.16 L/h for a 13-kg child. Age affected clearance, reaching 50% maturation at birth and 90% maturation at 8 months. Nondispersible tablets had 29% lower apparent oral bioavailability compared to dispersible tablets. Median exposures at current WHO-recommended doses were below the AUC target for children weighing 20 mg/kg are required to ensure adequate exposure. Further studies are needed to determine safety and tolerability of these higher doses.

Clofazimine is recommended for the treatment of rifampicin-resistant tuberculosis (RR-TB), but there is currently no verified dosing guideline for its use in children. There is only limited safety and no pharmacokinetic (PK) data available for children. We aimed to characterize clofazimine PK and its relationship with QT-interval prolongation in children. An observational cohort study of South African children

ATP-binding cassette (ABC) transporters are transmembrane proteins expressed commonly in metabolic and excretory organs to control xenobiotic or endobiotic disposition and maintain their homeostasis. Changes in ABC transporter expression may directly affect the pharmacokinetics of relevant drugs involving absorption, distribution, metabolism, and excretion (ADME) processes. Indeed, overexpression of efflux ABC transporters in cancer cells or bacteria limits drug exposure and causes therapeutic failure that is known as multidrug resistance (MDR). With the discovery of functional noncoding microRNAs (miRNAs) produced from the genome, many miRNAs have been revealed to govern posttranscriptional gene regulation of ABC transporters, which shall improve our understanding of complex mechanism behind the overexpression of ABC transporters linked to MDR. In this article, we first overview the expression and localization of important ABC transporters in human tissues and their clinical importance regarding ADME as well as MDR. Further, we summarize miRNA-controlled posttranscriptional gene regulation of ABC transporters and effects on ADME and MDR. Additionally, we discuss the development and utilization of novel bioengineered miRNA agents to modulate ABC transporter gene expression and subsequent influence on cellular drug accumulation and chemosensitivity. Findings on posttranscriptional gene regulation of ABC transporters shall not only improve our understanding of mechanisms behind variable ADME but also provide insight into developing new means towards rational and more effective pharmacotherapies.

INTRODUCTION: Dosing recommendations for hydromorphone intravenous constant rate infusion (IV CRI) are derived from simulations following IV bolus administration. While this extrapolated dose regimen has been described clinically, pharmacokinetics (PK) of hydromorphone infusions in dogs are not yet described. The study objective was to describe the PK of hydromorphone in healthy dogs receiving an IV bolus followed by an IV CRI for 48 h. METHODS: A prospective, experimental study was performed involving the administration of hydromorphone (0.1 mg/kg IV bolus then IV CRI 0.01 mg/kg/h over a 48 h period) to 6 healthy Beagle dogs. Blood samples were collected at 16 time points between 0 and 58 h relative to the initial bolus. Plasma hydromorphone concentrations were analyzed by high pressure liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic parameter estimates were obtained with compartmental methods using commercially available software. RESULTS: A two-compartment model with first order elimination was used. At the end of the infusion, median (range) plasma hydromorphone concentrations were 6.8 (5.5-19.6) ng/mL. The median total body clearance was 30.4 (19.8-36.7) mL/min/kg; volume of distribution at steady state was 4.5 (3.2-7.8) L/kg; and terminal elimination half-life was 11.2 (7.6-24.3) h. CONCLUSION: Hydromorphone (0.1 mg/kg IV bolus then IV CRI of 0.01 mg/kg/h) maintained steady-state plasma concentrations above the minimum human analgesic target in healthy Beagle dogs with minimal side effects. Further studies are needed to determine the effective plasma concentrations of hydromorphone in painful dogs.

INTRODUCTION: Understanding the pharmacokinetics and pharmacodynamics of fentanyl in horses is crucial for optimizing pain management strategies in veterinary medicine. METHODS: Six adult horses were enrolled in a randomized crossover design. Treatments included: placebo, two 100 mcg/h patches (LDF), four 100 mcg/h patches (MDF), and six 100 mcg/h patches (HDF). Patches were in place for 72 h. Blood was obtained for fentanyl plasma concentration determination, thermal threshold, mechanical threshold, heart rate, respiratory rate, and rectal temperature were obtained prior patch placement and at multiple time points following patch placement for the following 96 h. Fentanyl plasma concentration was determined using LC-MS/MS. Data were analyzed using a generalized mixed effects model. RESULTS: Mean (range) maximum plasma concentration (Cmax), time to Cmax, and area under the curve extrapolated to infinity were 1.39 (0.82-1.82), 2.64 (1.21-4.42), 4.11 (2.78-7.12) ng/ml, 12.7 (8.0-16.0), 12.7 (8.0-16.0), 12 (8.0-16.0) h, 42.37 (27.59-55.56), 77.24 (45.62-115.06), 120.34 (100.66-150.55) h ng/ml for LDF, MDF, and HDF, respectively. There was no significant effect of treatment or time on thermal threshold, mechanical threshold, respiratory rate, or temperature (p > 0.063). There was no significant effect of treatment on heart rate (p = 0.364). There was a significant effect of time (p = 0.003) on heart rate with overall heart rates being less than baseline at 64 h. CONCLUSIONS: Fentanyl administered via transdermal patch is well absorbed and well tolerated but does not result in an anti-nociceptive effect as measured by thermal and mechanical threshold at the doses studied.

Aims Methods Results Conclusions This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti‐interleukin (IL)‐33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data.The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab‐treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6 weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL‐33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed‐effect modelling approach.The final two‐compartment PK model with tozorakimab binding IL‐33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40–0.59, 1/day), 12.64 (90% CI: 8.60–18.62, L) and 0.87 (90% CI: 0.65–1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL‐33/sST2 levels was more than 95% at doses greater than 90 mg.The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose–response relationships and supporting clinical dose selection. [ABSTRACT FROM AUTHOR]

In recent years, the prevalence and fatality rates of atherosclerotic cardiovascular disease have not only shown a consistent rise that cannot be ignored, but have also become a pressing social health problem that requires urgent attention. While interventional surgery and drug therapy offer significant therapeutic results, they often come with common side effects. Geniposide, an active component extracted from the Chinese medicine Gardenia jasminoides Ellis, shows promise in the management of cardiac conditions. This review comprehensively outlines the underlying pharmacological mechanisms by which geniposide exerts its effects on atherosclerosis. Geniposide exhibits a range of beneficial effects including alleviating inflammation, inhibiting the development of macrophage foam cells, improving lipid metabolism, and preventing platelet aggregation and thrombosis. It also demonstrates mitochondrial preservation, anti-apoptotic effects, and modulation of autophagy. Moreover, geniposide shows potential in improving oxidative stress and endoplasmic reticulum stress by maintaining the body's antioxidant and oxidative balance. Additionally, this review comprehensively details the biological properties of geniposide, including methods of extraction and purification, as well as its pharmacokinetics and toxicological characteristics. It further discusses the clinical applications of related biopharmaceuticals, emphasizing the potential of geniposide in the prevention and treatment of atherosclerotic cardiovascular diseases. Furthermore, it highlights the limitations of current research, aiming to provide insights for future studies. Highlights: Geniposide is an active iridoid glycoside compound extracted from the Chinese medicine Gardenia jasminoides Ellis. Geniposide can combat atherosclerosis through various mechanisms. Geniposide modulates immune cells and the reverse cholesterol transport, thereby limiting the formation of macrophage foam cells and improving lipid metabolism. The effects of geniposide on autophagy and apoptosis in VSMCs may be the emphasis of additional research. Whether geniposide can regulate the interaction between apoptosis and autophagy in CVD needs further investigation. Whether geniposide can target intestinal flora to inhibit atherosclerosis development needs further investigation. By selecting an appropriate route of administration and dosage regimen for geniposide, potential safety concerns can be effectively addressed. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions To assess the effects of a small‐molecule nicotinamide N‐methyltransferase (NNMT) inhibitor, 5A1MQ, on body composition, metabolic variables, fatty liver pathologies, and circulating biomarkers in diet‐induced obese (DIO) mice, and characterize its plasma pharmacokinetics (PK) and tissue distribution in vivo.DIO mice were administered vehicle or 5A1MQ once daily for 28 days. Longitudinal measures of body composition, blood glucose and plasma insulin levels, and terminal measures of liver histopathology and serum markers, were evaluated. Plasma and tissue PK were established in age‐ and strain‐matched mice after intravenous, oral, and subcutaneous dosing of 5A1MQ.5A1MQ treatment dose‐dependently limited body weight and fat mass gains, improved oral glucose tolerance and insulin sensitivity, and suppressed hyperinsulinaemia in DIO mice. Liver histology from 5A1MQ‐treated DIO mice showed attenuated hepatic steatosis and macrophage infiltration, and correspondingly reduced liver weight, size, and triglyceride levels. 5A1MQ treatment normalized circulating levels of alanine transaminase, aspartate transaminase, and ketone bodies, supporting an overall improvement in liver and metabolic functions. The pharmacodynamic effects of 5A1MQ were further corroborated by its high systemic exposure and effective distribution to metabolically active tissues, including adipose, muscle and liver, following subcutaneous dosing of mice.This work validates NNMT inhibition as a viable pharmacological approach to ameliorate metabolic imbalances and improve liver pathologies that develop with obesity. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the pharmacokinetics (PKs) and safety of a generic drug, linezolid, compared to those of a reference drug in healthy Chinese subjects under both fasting and fed conditions. This was a randomized, open‐label, 2‐period, 2‐sequence crossover study. The subjects received a single dose of the test or reference drug, linezolid (600 mg), in each period. The PK parameters were calculated using a non‐compartmental method and compared between the 2 drugs. Bioequivalence was analyzed using geometric mean ratios (GMRs) of the 2 formulations and their corresponding 90% confidence intervals (CIs). The safety of the 2 formulations was assessed under both fasting and fed conditions. Forty‐eight subjects completed the study, 24 each in the fasting and feeding groups. The average plasma concentration‐time patterns of linezolid were similar for both medications under both conditions. The GMR and 90% CIs of the maximum plasma concentration and the area under the plasma concentration‐time curve of linezolid were ranged from 0.80 to 1.25. Both drugs were well tolerated with a similar incidence of adverse drug reactions. In conclusion, the PK and safety profiles of the 2 formulations were comparable. Food intake did not influence the PK profiles of linezolid. These results suggest that the test drug can be used as an alternative to reference drugs. [ABSTRACT FROM AUTHOR]

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open‐label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration‐time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single‐ and multiple‐dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment‐emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib. [ABSTRACT FROM AUTHOR]

Background: To assess the bioequivalence between Gan & Lee (GL) glargine U300 and Toujeo® regarding pharmacokinetics (PK), pharmacodynamics (PD), and safety in Chinese healthy male participants. Methods: A single-center, randomized, double-blind, single-dose, two-preparation, two-sequence, four-cycle repeated crossover design study was performed to compare GL glargine U300 and Toujeo® in 40 healthy participants. The primary PK endpoints were the area under the curve of glargine metabolites, M1 concentration from 0 to 24 hours (AUC0-24h), and the maximum glargine concentration within 24 hours post-dose (Cmax). The primary PD endpoints were the area under the glucose infusion rate (GIR) curve from 0 to 24 hours (AUCGIR.0-24h) and the maximum GIR within 24 hours post-dose (GIRmax). Results: GL Glargine U300 demonstrated comparable PK parameters (AUC0-24h, Cmax, AUC0-12h, and AUC12-24h of M1) and PD responses [AUCGIR.0--24h, GIRmax, AUCGIR.0-12h, and AUCGIR.12--24h] to those of Toujeo®, as indicated by 90% confidence intervals ranging from 80% to 125%. No significant disparities in safety profiles were observed between the two treatment groups, and there were no reported instances of serious adverse events. Conclusion: The PK, PD, and safety of GL glargine U300 were bioequivalent to that of Toujeo®. [ABSTRACT FROM AUTHOR]

Plant-derived phytochemicals from medicinal plants are becoming increasingly attractive natural sources of antimicrobial and antiviral agents due to their therapeutic value, mechanism of action, level of toxicity and bioavailability. The continued emergence of more immune-evasive strains and the rate of resistance to current antiviral drugs have created a need to identify new antiviral agents against SARS-CoV-2. This study investigated the antiviral potential of balsaminol, a bioactive compound from Momordica balsamina, and its inhibitory activities against SARS-CoV-2 receptor proteins. In this study, three Food and Drug Administration (FDA) COVID-19 approved drugs namely; nirmatrelvir, ritonavir and remdesivir were used as positive control. Molecular docking was performed to determine the predominant binding mode (most negative Gibbs free energy of binding/ΔG) and inhibitory activity of balsaminol against SARS-CoV-2 receptor proteins. The pharmacokinetics, toxicity, physicochemical and drug-like properties of balsaminol were evaluated to determine its potential as an active oral drug candidate as well as its non-toxicity in humans. The results show that balsaminol E has the highest binding affinity to the SARS CoV-2 papain-like protease (7CMD) with a free binding energy of − 8.7 kcal/mol, followed by balsaminol A interacting with the spike receptor binding domain (6VW1) with − 8.5 kcal/mol and balsaminol C had a binding energy of − 8.1 kcal/mol with the main protease (6LU7) comparable to the standard drugs namely ritonavir, nirmatrelvir and remdesivir. However, the ADMET and drug-like profile of balsaminol F favours it as a better potential drug candidate and inhibitor of the docked SARS-CoV-2 receptor proteins. Further preclinical studies are therefore recommended. [ABSTRACT FROM AUTHOR]

An environmentally friendly, versatile multicomponent reaction for synthesizing isoxazol-5-one and pyrazol-3-one derivatives has been developed, utilizing a freshly prepared g-C3N4·OH nanocomposite as a highly efficient catalyst at room temperature in aqueous environment. This innovative approach yielded all the desired products with exceptionally high yields and concise reaction durations. The catalyst was well characterized by FT-IR, XRD, SEM, EDAX, and TGA/DTA studies. Notably, the catalyst demonstrated outstanding recyclability, maintaining its catalytic efficacy over six consecutive cycles without any loss. The sustainability of this methodology was assessed through various eco-friendly parameters, including E-factor and eco-score, confirming its viability as a green synthetic route in organic chemistry. Additionally, the gram-scale synthesis verifies its potential for industrial applications. The ten synthesized compounds were also analyzed via a PASS online tool to check their several pharmacological activities. The study is complemented by in silico molecular docking, pharmacokinetics, and molecular dynamics simulation studies. These studies discover 5D as a potential candidate for drug development, supported by its favorable drug-like properties, ADMET studies, docking interaction, and stable behavior in the protein binding cavity. [ABSTRACT FROM AUTHOR]

AbstractModeling antioxidants for improved human health is a prime area of research. Inclusion complexes exhibit antioxidant activity. Supramolecular scaffolds like calixtyrosol are anticipated to have considerable antioxidant and therapeutic activity. In this study, we have designed 30 polyphenolic metacyclophanes and investigated their antioxidant properties. Exceptional O─H bond dissociation energy of 44 kcal/mol is reported for a metacyclophane with acyl urea linkage. This may be explained through a cooperative effect of localization of spin density distribution and an intramolecular hydrogen bonding of the corresponding radical. Further, the pharmacokinetics and toxicity analysis screened eight drug-like candidates. The interaction of the eight screened molecules with the Lysozyme transport protein and SOD protein has been studied using the molecular docking approach. Lastly, the MD simulations are performed to analyze the conformational changes of the transport protein after complexation with the proposed molecules. Comprehensive analyses including density functional studies of physiological parameters, favorable pharmacokinetics, toxicity, molecular docking, and MD simulations affirmed polyphenolic metacyclophane XXI as a radical scavenging and drug-like candidate. [ABSTRACT FROM AUTHOR]