Model-Informed Precision Dosing of Isoniazid: Parametric Population Pharmacokinetics Model Repository.

Introduction: Isoniazid (INH) is a crucial first-line anti tuberculosis (TB) drug used in adults and children. However, various factors can alter its pharmacokinetics (PK). This article aims to establish a population pharmacokinetic (popPK) models repository of INH to facilitate clinical use. Methods: A literature search was conducted until August 23, 2022, using PubMed, Embase, and Web of Science databases. We excluded published popPK studies that did not provide full model parameters or used a non-parametric method. Monte Carlo simulation works was based on RxODE. The popPK models repository was established using R. Non-compartment analysis was based on IQnca. Results: Fourteen studies included in the repository, with eleven studies conducted in adults, three studies in children, one in pregnant women. Two-compartment with allometric scaling models were commonly used as structural models. NAT2 acetylator phenotype significantly affecting the apparent clearance (CL). Moreover, postmenstrual age (PMA) influenced the CL in pediatric patients. Monte Carlo simulation results showed that the geometric mean ratio (95% Confidence Interval, CI) of PK parameters in most studies were within the acceptable range (50.00-200.00%), pregnant patients showed a lower exposure. After a standard treatment strategy, there was a notable exposure reduction in the patients with the NAT2 RA or nonSA (IA/RA) phenotype, resulting in a 59.5% decrease in AUC0-24 and 83.2% decrease in Cmax (Infants), and a 49.3% reduction in AUC0-24 and 73.5% reduction in Cmax (Adults). Discussion: Body weight and NAT2 acetylator phenotype are the most significant factors affecting the exposure of INH. PMA is a crucial factor in the pediatric population. Clinicians should consider these factors when implementing model-informed precision dosing of INH. The popPK model repository for INH will aid in optimizing treatment and enhancing patient outcomes.

Escitalopram population pharmacokinetics and remedial strategies based on CYP2C19 phenotype.

BACKGROUND AND PURPOSE: CYP2C19 is a key factor influencing escitalopram (SCIT) exposure. However, different studies reported various results. This study aims to develop a population pharmacokinetic (popPK) model characterizes the disposition of SCIT in the Chinese population. Based on the popPK model, the study simulates non-adherence scenarios and proposes remedial strategies to facilitate SCIT personalized therapy. METHODS: Nonlinear mixed-effects modeling using data from two Chinese bioequivalence studies was employed. Monte-Carlo simulation was used to explore non-adherence scenarios and propose remedial strategies based on the proportion of time within the therapeutic window. RESULTS: Results showed that a one-compartment model with transit absorption and linear elimination described the data well, CYP2C19 phenotypes and weight were identified as significant covariates impacting SCIT exposure. Patients were recommended to take the entire delayed dose immediately if the delay time was no >12 h, followed by the regular regimen at the next scheduled time. When there is one or two doses missed, taking a double dose immediately was recommended to the CYP2C19 intermediate and extensive population, and a 1.5-fold dose was recommended to the CYP2C19 poor metabolizers with the consideration of adverse effects. LIMITATION: All samples were derived from the homogenized Chinese healthy population for model building, which may pose certain constraints on the ability to identify significant covariates, such as age. CONCLUSION: The study highlights the importance of considering patient characteristics for personalized medication and offers a unique perspective on utilizing the popPK repository in precision dosing.

Escitalopram Personalized Dosing: A Population Pharmacokinetics Repository Method.

Escitalopram (SCIT) represents a first-line antidepressant and antianxiety medication. Pharmacokinetic studies of SCIT have demonstrated considerable interindividual variability, emphasizing the need for personalized dosing. Accordingly, we aimed to create a repository of parametric population pharmacokinetic (PPK) models of SCIT to facilitate model-informed precision dosing. In November 2022, we searched PubMed, Embase, and Web of Science for published PPK models and identified eight models. All the structural models reported in the literature were either one- or two-compartment models. In order to investigate the variances in model performance, the parameters of all PPK models were derived from the literature published. A representative virtual population, characterized by an age of 30, a body weight of 70 kg, and a BMI of 23 kg/m2, was generated for the purpose of replicating these models. To accomplish this, the rxode2 package in the R programming language was employed. Subsequently, we compared simulated concentration-time profiles and evaluated the impact of covariates on clearance. The most significant covariates were CYP2C19 phenotype, weight, and age, indicating that dosing regimens should be tailored accordingly. Additionally, among Chinese psychiatric patients, SCIT showed nearly double the exposure compared to other populations, specifically when considering the same CYP2C19 population restriction, which is a knowledge gap that needs further investigation. Furthermore, this repository of parametric PPK models for SCIT has a wide range of potential applications, like design miss or delay dose remedy strategies and external PPK model validation.

Pharmacokinetics and Bioequivalence Evaluation of 2 Formulations of Tenofovir Alafenamide.

The study was conducted to compare the pharmacokinetics and safety profiles of 2 brands of tenofovir alafenamide (TAF) fumarate tablets. This research was a 2-preparation, 2-sequence, 4-period crossover, completely replicated study in 68 healthy Chinese subjects under fasting and fed conditions. The mean values of the area under the concentration-time curve from time 0 to the last time point with blood sample collection (AUC0-t ), area under the concentration-time curve from time 0 to infinity (AUC0-∞ ), and maximum concentration (Cmax ) for the test and reference products of TAF were 248.5 and 275.7 ng/mL, 148.1 and 157.8 ng • h/mL, and 148.4 and 158.1 ng • h/mL, respectively, under the fasting condition. On the other hand, the mean value of Cmax , AUC0-t , and AUC0-∞ for the test and reference formulations of TAF were 244.6 and 246.7 ng/mL, 230.4 and 244.9 ng • h/mL, and 233.2 and 246.2 ng • h/mL, respectively, under the fed condition. The 90% confidence intervals for geometric mean ratios of AUC0-t and AUC0-∞ of TAF in fasting and fed states were within the bioequivalence acceptance limits when tested using the average-bioequivalence method. The point estimate value for geometric mean ratio of Cmax in fasting and fed states (88.4% and 95.5%, respectively) were within the bioequivalence acceptance limits as per the reference-scaled average-bioequivalence method. The safety profiles of the 2 formulations were comparable. Pharmacokinetic analysis demonstrated that the test formulations of TAF exhibited bioequivalence to the reference and were well tolerated by healthy Chinese subjects (Study Registry Identification Number: CTR20190086; CTR20190087).

Pharmacokinetics and Safety of Dapoxetine Hydrochloride in Healthy Chinese Men: Impact of Dose and High-Fat Meal.

Dapoxetine is the first oral medication specifically developed for the on-demand treatment of premature ejaculation. The pharmacokinetics and safety of 30 mg (n = 40) and 60 mg (n = 38) dapoxetine in healthy Chinese under fasted and fed states were assessed in 2 studies. Both studies are random, single-center, 2-period, open-label, 2-way crossover designs. Plasma concentration of dapoxetine was determined by high-performance liquid chromatography-tandem mass spectrometry, and the pharmacokinetic parameters were calculated using noncompartmental analysis. Dapoxetine was quickly absorbed and reached maximum concentration 1 to 3 hours after oral administration. Elimination was biphasic, and the plasma concentration decreased to 3% to 7% of maximum concentration by 24 hours while half-life was 15 to 18 hours. Meantime, high-fat meals slightly increased its exposure. Both doses of dapoxetine were well tolerated. The adverse events in the high-dose group under fasted and fed states were 37.9% and 19.0%, respectively.

Bioequivalence Analysis of 2 Dapoxetine Hydrochloride Formulations in Healthy Chinese Male Volunteers Under Fed and Fasting Conditions: A Randomized, Open-Label, 2-Sequence, 2-Period, 2-Way Crossover Study.

This study assessed whether the reference and test formulations of dapoxetine hydrochloride were bioequivalent under fed and fasting conditions postadministration of a single dose as well as evaluated the safety profile of these 2 formulations. This study was a randomized, single-center, 2-period, open-label, 2-way crossover design study with a washout period of 7 days between each period. The study included 80 subjects, 40 under fed and 40 under fasting conditions. During each study period, the subjects were administered a single oral dose of either the reference or the test formulation, followed by collection of plasma samples 70 hours postdose. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was performed to determine the concentrations of dapoxetine in plasma samples along with the calculation of Cmax , AUC0-t, and AUC0-inf . In addition, adverse events were monitored to determine the safety of these formulations. The geometric mean ratio (90%CI) for the reference and test formulations was 86% to 100%, 89% to 103%, and 89% to 103% under fasting conditions and 92% to 107%, 91% to 100%, and 92% to 101% under fed conditions for Cmax , AUC0-t , and AUC0-inf , respectively. The 90%CIs for the test/reference ratio for AUC and Cmax were within the acceptable limits of bioequivalence, thus demonstrating bioequivalence for these 2 dapoxetine hydrochloride formulations.

Evaluation of Bioequivalency and Pharmacokinetic Parameters for Two Formulations of Glimepiride 1-mg in Chinese Subjects.

PURPOSE: Glimepiride, an FDA-approved oral hypoglycemic drug, is a long-acting sulfonylurea (SU), used for treating type 2 diabetes. The study aimed to evaluate the bioequivalence and safety profiles of two different formulations of glimepiride 1 mg from two different manufactures in healthy Chinese subjects in the fasting and fed state in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation. PATIENTS AND METHODS: This study is an open-label, two-period, two-sequence, randomized, two-way crossover pharmacokinetic study in healthy Chinese subjects in the fasting and fed state. Seventy-two subjects were randomly assigned to the fasting group and the fed group (n=36 each). We collected blood samples, 24-h post drug administration. The plasma concentration of glimepiride was assessed using HPLC coupled with mass spectrometry. The following parameters were evaluated: AUC0-inf, AUC0-last, Cmax, t1/2, Tmax, and λz. Safety was determined based on the occurrence of adverse events (AEs) and laboratory examinations (biochemistry, hematology, and urinalysis) throughout the entire study period. RESULTS: The geometric mean ratios (GMR) amongst the two glimepiride formulations for the primary pharmacokinetic parameters, ie, AUC0-inf, AUC0-last, and Cmax as well as the corresponding 90% CIs, were all within the range of 80.00-125.00% in the fasting and fed state. The safety profile for both treatments was comparable. CONCLUSION: PK analysis revealed that the test and reference formulations of glimepiride were bioequivalent and well tolerated in healthy Chinese subjects. Chinese Clinical Trials Registry identifier: CTR20171121. CLINICAL TRIAL REGISTRATION NUMBER: CTR20171121.