Effects of CYP3A4*1G and CYP3A5*3 polymorphisms on pharmacokinetics of tylerdipine hydrochloride in healthy Chinese subjects.

The aim of this analysis was to explore the influence of CYP3A4*1G and CYP3A5*3 polymorphisms on the pharmacokinetics of tylerdipine in healthy Chinese subjects. A total of 64 and 63 healthy Chinese subjects were included and identified as the genotypes of CYP3A4*1G and CYP3A5*3, respectively. Plasma samples were collected for up to 120 h post-dose to characterize the pharmacokinetic profile following single oral dose of the drug (5, 15, 20, 25 and 30 mg). Plasma levels were measured by a high-performance liquid chromatography-mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated using non-compartmental method. The maximum concentration (Cmax) and the area under the curve (AUC0-24 h) were all corrected by the dose given. In the wild-type group, the mean dose-corrected AUC0-24 h was 1.35-fold larger than in CYP3A4*1G carriers (p = .018). Among the three CYP3A5 genotypes, there showed significantly difference (p = .008) in the t1/2, but no significant difference was observed for the AUC0-24 h and Cmax. In subjects with the CYP3A5*3/*3 genotype, the mean t1/2 was 1.35-fold higher than in CYP3A5*1/*1 group (p = .007). And the t1/2 in CYP3A5*3 carriers also was 1.32-fold higher than in the wild-type group (p = .004). CYP3A4*1G and CYP3A5*3 polymorphisms may influence tylerdipine pharmacokinetic in healthy Chinese subjects.

Randomized, double-blind, placebo-controlled, multiple-dose study of the safety, tolerability and pharmacokinetics of benvitimod, a candidate drug for the treatment of psoriasis.

WHAT IS KNOWN AND OBJECTIVE: Benvitimod is a newly synthesized non-steroidal small molecule, aimed at the treatment for psoriasis. Several trials have demonstrated that benvitimod improves plaque psoriasis. However, its maximum tolerated dose and pharmacokinetic characteristics have not been reported on. The goals of this study were to evaluate the safety, tolerability and pharmacokinetics of benvitimod after topical administration in healthy subjects. METHODS: This phase I trial in healthy subjects was designed as a randomized, double-blind, placebo-controlled, ascending-dose study. After screening and randomization, 56 volunteers received benvitimod (0·5-2·0%) or placebo cream once or twice daily. Doses were escalated from 5 to 30 mg daily in six cohorts. Safety and tolerability were appraised by monitoring adverse events and laboratory parameters. Benvitimod concentrations were measured using liquid chromatography-tandem-mass spectrometry. RESULTS AND DISCUSSION: Exposure to benvitimod did not result in electrocardiographic or clinical laboratory changes. Doses up to 30 mg were well tolerated. All adverse events were mild. Adverse effects at the application site were observed in subjects randomized to benvitimod 5 mg q.d and b.i.d, but there were no observable dose effects in the dose-range evaluated. Benvitimod was detected in fewer than 5% of the plasma samples. WHAT IS NEW AND CONCLUSIONS: Benvitimod cream, at single doses of up to 30 mg, is well tolerated by healthy subjects. Following topical application, systemic absorption was negligible.

Bioequivalence and Food Effect Assessment of Eltrombopag Olamine Tablets in Healthy Chinese Subjects: An Open, Randomized, Single-Dose, and Two-Period Crossover Study.

Eltrombopag, a nonpeptide thrombopoietin receptor agonist, is primarily used for treating immune thrombocytopenic purpura. The aim of this study was to investigate the pharmacokinetic profile and food-drug interaction of test and reference eltrombopag olamine tablets among healthy Chinese volunteers. An open, randomized, single-dose, 2-period crossover design was employed, involving fasting and fed conditions with a 10-day washout period. Ninety-six healthy volunteers received a single oral dose of 25 mg of the 2 eltrombopag formulations, with 48 participants in each group: fasting volunteers and those consuming a high-fat, low-calcium meal. Plasma eltrombopag concentrations were analyzed using liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters were derived from the concentration-time profiles. The geometric mean ratios, with 90% confidence intervals, for the maximum plasma concentration, area under the concentration-time curve from time 0 to the last measurable concentration, and area under the concentration-time curve from time 0 to infinity fell within the bioequivalence acceptance criteria (80%-125%) under both fasting and fed conditions, indicating bioequivalence between the test and reference formulations. Administration of eltrombopag with a high-fat, low-calcium diet reduced the net systemic exposure by approximately 40%. Adverse events were recorded, and no serious adverse events were observed in either fasting or fed conditions. In conclusion, eltrombopag is well tolerated and exhibits a favorable safety profile in the Chinese population. The achievement of bioequivalence under fasting and fed conditions supports the demonstration of biosimilarity between the test and reference formulations.

Population Pharmacokinetic Analysis of Valsartan in Healthy Chinese Subjects.

The study was conducted to establish a population pharmacokinetic (PPK) model of valsartan in Chinese healthy subjects and investigate potential covariate impacts on the pharmacokinetics (PK) parameters. Data from a bioequivalence study with 78 Chinese healthy subjects were retrospectively analyzed to develop a PPK model of valsartan. Phoenix NLME 8.1 was used to build a PPK model and quantify the effects of covariates, such as demographic data and biochemical, on the PK parameters of valsartan. For the healthy Chinese population, valsartan conformed to the two-compartment model with an absorption lag time. In the final PPK model, food affected the absorption rate constant, while aspartate aminotransferase, alanine aminotransferase, and creatinine affected the clearance of the central compartment. The final PPK model was verified to be reproducible, and it can be used to evaluate the PK parameters. This is the first research describing the PPK profile of valsartan in healthy Chinese subjects, and it is expected to provide relevant PK parameters for further study of valsartan.

Bioequivalence Study of Epalrestat for Healthy Chinese Subjects.

Epalrestat is a reversible noncompetitive inhibitor of aldose reductase with selective inhibition of aldose reductase. It can inhibit the accumulation of sorbitol in red blood cells in patients with diabetic peripheral neuropathy and can improve patients' conscious symptoms and neurological dysfunction. This study was designed to evaluate the bioequivalence in healthy Chinese subjects of a new test formulation and reference formulation of oral epalrestat (50 mg) in the fasting state. The study was performed with 44 healthy Chinese subjects according to a randomized 2-way crossover design. The main pharmacokinetic parameters of test formulation and reference formulation as follows: 4793 and 4781 ng/mL for maximum plasma concentration, 8556 and 8431 ng h/mL for area under the plasma concentration-time curve extrapolated to infinity. The test formulation of epalrestat was bioequivalent to the reference formulation. The bioequivalence study of epalrestat in healthy Chinese subjects suggests that the test and reference formulations have similar pharmacokinetics and both formulations are well tolerated in the dose range studied in healthy Chinese subjects. All these findings provided valuable pharmacokinetic knowledge for further clinical development.

Corrigendum: Pharmacokinetics and bioequivalence study of esomeprazole magnesium enteric-coated tablets 20 mg in healthy Chinese subjects under fasting and fed conditions.

[This corrects the article DOI: 10.3389/fphar.2023.1169103.].

Pharmacokinetics and bioequivalence study of esomeprazole magnesium enteric-coated tablets 20 mg in healthy Chinese subjects under fasting and fed conditions.

Objective: The main purpose of this study was to evaluate the pharmacokinetics, bioequivalence, and safety properties between a new generic and a brand reference formulation of esomeprazole enteric-coated tablets 20 mg in healthy Chinese subjects under fasting and fed conditions. Methods: The fasting study was an open-label, randomized, two-period crossover study conducted in 32 healthy Chinese volunteers, and the fed study was a four-period crossover study conducted in 40 healthy Chinese volunteers. Blood samples were collected at the specified time points and determined to obtain the plasma concentrations of esomeprazole. The primary pharmacokinetic parameters were calculated using the non-compartment method. Bioequivalence was analyzed by the geometric mean ratios (GMRs) of the two formulations and the corresponding 90% confidence intervals (CIs). The safety of the two formulations was assessed. Results: The fasting and fed study showed that the pharmacokinetics of the two formulations was similar. Under the fasting condition, the 90% CIs of GMRs of the test-to-reference formulation were 87.92%-104.36% for Cmax, 87.82%-101.45% for AUC0-t, and 87.99%-101.54% for AUC0-∞; under the fed condition, the 90% CIs of GMRs of the test-to-reference formulation were 80.53%-94.95% for Cmax, 87.46%-97.26% for AUC0-t, and 87.46%-97.16% for AUC0-∞. The 90% CIs of GMRs fall within the bioequivalence range of 80.00%-125.00%. The two formulations had good safety and were well-tolerated, and no serious adverse events occurred. Conclusion: According to relevant regulatory standards, esomeprazole enteric-coated generic and reference products exhibited bioequivalence and good safety in healthy Chinese subjects. Clinical Trials Registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20171347 and CTR20171484.

Pharmacokinetics and Bioequivalence Studies of Roxatidine Acetate Hydrochloride Sustained-Release Capsule in Healthy Chinese Subjects.

This study aimed to evaluate the bioequivalence between a generic roxatidine acetate hydrochloride (RAH) sustained-release capsule and brand-named formulation (ALTAT) under fasting and fed conditions. An open-label, single-center, randomized 2-period crossover study with a 5-day washout period was conducted. A single oral dose of 75-mg generic RAH sustained-release capsule (test drug) or a commercial capsule (reference drug) was given to healthy volunteers under fasting (n = 36) and fed conditions (n = 36). Blood samples were collected at baseline and during the 24 hours after dosing. The concentrations of roxatidine acetate (ROX) and bioactive metabolite roxatidine in plasma were detected using a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were analyzed with noncompartmental methods. As prodrug, RAH was dehydrochloric acid to ROX in body and further rapidly converted to roxatidine. Such a rapid metabolism resulted in ROX that was hardly detected in plasma. Active metabolism roxatidine was therefore used to evaluate the pharmacokinetic process. The major pharmacokinetic parameters of roxatidine including peak plasma concentration, area under the plasma concentration-time curve from time 0 to time t, and area under the plasma concentration-time curve from time 0 to infinity were similar between the 2 preparations under fasting and fed conditions. The generic RAH sustained-release capsule is bioequivalent to the reference drug under fasting and fed conditions in healthy Chinese subjects.

Pharmacokinetics and Safety of Doripenem in Healthy Chinese Subjects and Monte Carlo Dosing Simulations.

The aim of this study was to investigate the pharmacokinetics (PK) of doripenem in healthy Chinese subjects and evaluate the optimal dosage regimens of doripenem. A randomized, single-dose, three-period, self-crossover controlled extended-infusion clinical trial was conducted with 12 healthy Chinese subjects. Plasma and urine samples were collected to determine doripenem concentrations. Non-compartmental and population PK analysis were performed to characterize the PK of doripenem. The Monte Carlo simulation was employed to optimize dosing regimens based on the probability of target attainment of doripenem against pathogens with different minimum inhibitory concentrations (MIC). All 12 healthy Chinese subjects completed the study, and the doripenem was well tolerated. The study showed linearity relationships in the peak plasma concentration and the area under the concentration-time curve after intravenous infusion of doripenem from 0.25 g to 1.0 g. The cumulative urinary recovery rate of doripenem was 68.1-72.0% within 24 h. PPK modeling showed a two-compartmental model, with first-order elimination presenting the best fit for doripenem PK. Monte Carlo simulation results showed that 1.0 g q12h or 0.5 g q8h was an optimal regimen for pathogens susceptible to doripenem (MIC ≤ 1 mg/L); while high dose and extended infusion (1 g, q8h, 4 h infusion) was proposed for unsusceptible pathogens (2 ≤ MIC ≤ 8 mg/L). In the dose range of 0.25 to 1.0 g, doripenem showed linear pharmacokinetics. Doripenem at 1.0 g with a prolonged infusion time of 4 h was predicted to be effective against pathogens with MICs as high as 8 mg/L.

Characteristics of the Ciliary Body in Healthy Chinese Subjects Evaluated by Radial and Transverse Imaging of Ultrasound Biometric Microscopy.

Background: The imaging and analysis of the ciliary body (CB) are valuable in many potential clinical applications. This study aims to demonstrate the anatomy characteristics of CB using radial and transverse imaging of ultrasound biometric microscopy (UBM) in healthy Chinese subjects, and to explore the determining factors. Methods: Fifty-four eyes of 30 healthy Chinese subjects were evaluated. Clinical data, including age, body mass index (BMI), intraocular pressure (IOP), axial length (AL), and lens thickness (LT), were collected. Radial and transverse UBM measurements of the ciliary body were performed. Anterior chamber depth (ACD), ciliary sulcus diameter (CSD), ciliary process length (CPL), ciliary process density (CPD), ciliary process area (CPA), ciliary muscle area (CMA), ciliary body area (CBA), ciliary body thickness (CBT0, CBT1, and CBTmax), anterior placement of ciliary body (APCB), and trabecular-ciliary angle (TCA) of four (superior, nasal, inferior, and temporal) quadrants were measured. Results: The average CPL was 0.513 ± 0.074 mm, and the average CPA was 0.890 ± 0.141 mm2. CPL and CPA tended to be longer and larger in the superior quadrant (p < 0.001) than in the other three quadrants. Average CPL was significantly correlated with AL (r = 0.535, p < 0.001), ACD (r = 0.511, p < 0.001), and LT (r = −0.512, p < 0.001). Intraclass correlation coefficient (ICC) scores were high for CPL (0.979), CPD (0.992), CPA (0.966), CMA (0.963), and CBA (0.951). Conclusions: In healthy Chinese subjects, CPL was greatest in the superior quadrant, followed by the inferior, temporal, and nasal quadrants, and CPA was largest in the superior quadrant, followed by the tempdoral, inferior, and nasal quadrants. Transverse UBM images can be used to measure the anatomy of the ciliary process with relatively good repeatability and reliability.

Comparison of the Pharmacokinetics of Generic Versus Branded Obeticholic Acid in a Chinese Population: Effects of Food and Sex.

The present study assessed the pharmacokinetics and bioequivalence of a single 10-mg dose of a generic and the branded formulation (Ocaliva) of obeticholic acid (OCA) in healthy Chinese subjects under fasting and fed conditions. The possible effects of food and sex on the pharmacokinetics of OCA and its 2 active metabolites (glyco-OCA and tauro-OCA) were evaluated. Plasma concentrations of OCA and its 2 active metabolites were measured by liquid chromatography-tandem mass spectrometry. The 90%CIs of the ratios of the test and reference formulations for Cmax , AUC0-t , and AUC0-∞ of OCA, glyco-OCA, and tauro-OCA were contained entirely within the 80% to 125% range required for bioequivalence under fasting and fed conditions. Plasma exposure of OCA was 30% to 36% higher under fed compared with fasting conditions. Plasma exposure of OCA, glyco-OCA, and tauro-OCA was 39% to 66%, 22% to 58%, and 37% to 84% higher, respectively, in women compared with men under fasting and fed conditions. In conclusion, OCA was well tolerated in healthy Chinese subjects under fasting and fed conditions. The single 10-mg dose of a generic OCA formulation was bioequivalent to Ocaliva. Food and sex impacted the pharmacokinetics of OCA and/or its 2 active metabolites. Further studies are required to determine if these effects are clinically relevant.

A Euglycemic Glucose Clamp Study to Evaluate the Bioavailability of LY2963016 Relative to Insulin Glargine in Healthy Chinese Subjects.

Insulin glargine (IGlar) and LY2963016 (LY IGlar) are long-acting insulin analogs with identical primary amino acid sequences. We conducted a randomized, open-label, 2-treatment, 2-period, crossover study in healthy Chinese subjects to evaluate the relative bioavailability of LY IGlar to IGlar and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of LY IGlar. Subjects (n = 58) were randomized to receive single subcutaneous doses (0.5 U/kg) of LY IGlar and IGlar with a ≥7-day washout period between study treatments. Serum was collected before and up to 24 hours after dosing to assess PK characteristics. PD characteristics were assessed by euglycemic clamp up to 24 hours after dosing. Linear mixed-effects models were used to fit the log-transformed primary PK (maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours) and PD parameters (maximum glucose infusion rate and total amount of glucose infused during clamp period). The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar for maximum observed concentration and area under the concentration-time curve from time 0 to 24 hours were 0.961 (0.887-1.04) and 0.941 (0.872-1.01), respectively. The geometric least squares means ratios (90% confidence interval) of LY IGlar to IGlar were 0.91 (0.85-0.98) for maximum glucose infusion rate and 0.89 (0.82-0.97) for total amount of glucose infused during clamp period. LY IGlar demonstrated similarity to IGlar in PK and PD characteristics following single-dose (0.5 U/kg) administration in healthy Chinese subjects.

Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: A Pharmacokinetics, Pharmacodynamics, and Safety Study.

INTRODUCTION: Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with high affinity and reverses its anticoagulant effect. This study investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab in healthy Chinese subjects at steady state of dabigatran and explored the effect of idarucizumab on PK and PD of dabigatran. METHODS: Twelve subjects received dabigatran etexilate treatment alone (220 mg twice daily, b.i.d., oral). After a washout period, the 12 subjects again received dabigatran etexilate (220 mg b.i.d., oral) and idarucizumab (2.5 + 2.5 g, intravenous) 2 h after the last administration of dabigatran etexilate. RESULTS: The geometric mean (gMean) values of area under the plasma concentration-time curve (AUC0-∞) and maximum concentration (Cmax) were 44,200 nmol h/L and 30,900 nmol/L, respectively. An amount of 35.3 µmol of idarucizumab, corresponding to 33.8% of the total dose, was excreted by urine over 72 h. The area under the effect (AUECabove,2-12) in the presence and absence of idarucizumab was close to zero for all coagulation parameters, diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT), which indicated the reversal of dabigatran anticoagulation by idarucizumab. There were no serious adverse events reported in this study. No subject tested positive for anti-idarucizumab antibodies. CONCLUSION: Idarucizumab was well tolerated and no subject tested positive for anti-idarucizumab antibodies in this study. PK and PD of idarucizumab in healthy Chinese subjects at a steady state of dabigatran were comparable with those in Japanese and Caucasian subjects. CLINICAL REGISTRATION: ClinicalTrials.gov Identifier No. NCT03086356.

Pharmacokinetic Profile of a Generic Formulation of Sofosbuvir and Its Metabolite GS-331007 in Healthy Chinese Subjects.

Sofosbuvir is an NS5B nucleotide inhibitor for the treatment of hepatitis C viral infection. In this study the pharmacokinetics (PK) and safety of single and multiple doses of generic sofosbuvir were investigated in healthy Chinese subjects. Twelve subjects (6 male and 6 female) were enrolled in this study. The PK parameters of sofosbuvir and its metabolite (GS-331007) in both blood and urine samples were analyzed after dosing by the established liquid chromatography tandem mass spectrometry analytical method. The safety/tolerability assessment consisted of documenting adverse events, vital signs, electrocardiogram, and laboratory test results. Sofosbuvir was well tolerated. Major PK parameters of the generic formulation of sofosbuvir were similar to those found in previous reports. These data support further clinical evaluation of this generic formulation of sofosbuvir.

Effects of a High-fat Meal on the Pharmacokinetics of the VEGFR Inhibitor Fruquintinib: A Randomized Phase I Study in Healthy Subjects.

PURPOSE: Fruquintinib is a potent and highly selective oral small-molecule tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and demonstrates promising activity against a broad spectrum of cancer types. The objective of the study was to investigate the tolerability and effect of high-fat food on the pharmacokinetic profile of a fruquintinib capsule in healthy Chinese subjects. METHODS: Healthy Chinese male subjects aged between 18 and 45 years were enrolled in the study. The study included 2 phases: a dose-escalation phase and a food effect-assessment phase. In the dose-escalation phase, subjects were administered a single dose of fruquintinib (2, 3, or 4 mg) in the fasted state. In the food effect-assessment phase, subjects were administered a 4-mg fruquintinib capsule in the fasted and fed states, respectively, in 2 cycles. Blood samples for pharmacokinetic analysis were collected at the designated time points. Tolerability was assessed throughout the study by physical examination including vital sign measurements, clinical laboratory tests, 12-lead ECG, clinical assessments, and monitoring for and spontaneous reporting of adverse events. FINDINGS: Twenty-nine eligible male subjects were enrolled in the study, including 9 in the dose-escalation phase and 20 in the food effect-assessment phase. In the food effect-assessment phase, the ratios (90% CI) of the geometric mean AUC0-∞ and Cmax values for fruquintinib in the fed state to those observed in the fasted state were 97.2% (94.0%-100.4%) and 82.9% (76.7%-89.5%), respectively. The mean (SD) Tmax values of fruquintinib were 3.0 (1.0) and 5.6 (4.5) hours in the fasted and fed states, respectively. The most common adverse events possibly related to the study drug were elevated blood uric acid, diarrhea, and decreased white blood cell count. IMPLICATIONS: The overall bioavailability of the evaluated formulation of fruquintinib was not affected by the consumption of a high-fat, high-calorie meal prior to dosing. However, the consumption of a high-fat, high-calorie meal prior to dosing prolonged the Tmax. These results indicate that the fruquintinib capsule can be administered with or without food. ClinicalTrials.gov identifier: NCT01955304.