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Chiglitazar is a novel configuration-restricted non-thiazolidinedione peroxisome proliferator-activated receptor pan-agonist currently in the Phase III clinical development stage for type 2 diabetes mellitus patients. The objective of this Phase I study was to evaluate the pharmacokinetics, safety and tolerability of single and multiple doses of chiglitazar tablets taken orally and the effect of food on its pharmacokinetics in healthy Chinese subjects. A single-centre, open-label, randomised, two-stage Phase I study was carried out. In the first-stage study, we evaluated a single dose of 8, 16, or 32 mg, and multiple doses of 16 mg, taken once daily for 9 days. The effect of food consumption was also studied in this stage. In the second-stage study, a greater range of single doses (24, 48 or 72 mg) were further evaluated. Pharmacokinetics, safety and tolerability profiles were assessed at each study stage. After a single oral dose of chiglitazar, at doses ranging from 8 to 72 mg, the maximum plasma concentration (Cmax) and area under the concentration–time curve (AUC) were proportionally increased (165–1599 ng/mL for the mean Cmax and 1356–12,584 ng·h/mL for the mean AUC0−t), with low inter-subject variability. There were no significant changes in the mean terminal phase half-life (t1/2), which ranged from 9.0 to 11.9 h, and the clearance and volume of distribution were similar for all evaluated doses. The results from the examination of multiple dose of 16 mg once daily for nine consecutive days showed that a steady-state condition was achieved by Day 6. There was no apparent accumulation of chiglitazar observed at Day 9, as compared with the first administration. While food increased the AUC0−t of chiglitazar by about 13%, there were no effects on other parameters, including Cmax, Tmax and t1/2. There were no serious or severe adverse events observed in the single- or multiple-dose studies. Chiglitazar tablets showed a good dose-dependent linear pharmacokinetic profile in the dose range of 8–72 mg. There was no accumulation after multiple daily administration of chiglitazar at a dose of 16 mg. High-fat/calorie food increased the absorption of the drug, but there were no significant changes in exposure and other pharmacokinetic parameters. Chiglitazar was safe and well tolerated in healthy Chinese subjects at the dose levels and administration regimens evaluated.

Ezetimibe/simvastatin combination tablet has been approved for the treatment of high low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or mixed hypercholesterolaemia as adjunctive therapy to diet, when diet alone is insufficient in lowering cholesterol. The aims of this study were to assess the pharmacokinetics and safety of an ezetimibe/simvastatin combination tablet after oral single-dose administration in healthy Chinese subjects including sex-related differences in pharmacokinetics.This was an open-label, single-dose study. Twelve healthy subjects (six males and six females) received a single dose of an ezetimibe/simvastatin combination tablet (ezetimibe 10 mg and simvastatin 40 mg). The pharmacokinetic parameters for ezetimibe and simvastatin were assessed by determining total ezetimibe, free ezetimibe, simvastatin and simvastatin acid concentrations using a validated liquid chromatography-tandem mass spectrometry method. Safety was evaluated by monitoring adverse events, laboratory assays, vital signs, physical examinations and 12-lead electrocardiograms.The pharmacokinetic parameters (mean ± SD) for total ezetimibe and free ezetimibe following a single dose were: maximum plasma drug concentration (C(max)) 81.56 ± 26.62 and 9.40 ± 6.17 ng/mL; time to reach C(max) (t(max)) 0.93 ± 0.30 and 1.25 ± 1.27 h; elimination half-life (t(½)) 24.32 ± 13.27 and 18.90 ± 9.66 h, and mean area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC(last)) 579.06 ± 241.45 and 126.01 ± 69.01 ng·h/mL, respectively. The pharmacokinetic parameters (mean ± SD) for simvastatin and simvastatin acid following a single dose were: C(max) 11.92 ± 5.50 and 3.37 ± 1.78 ng/mL, t(max) 0.98 ± 0.28 and 3.73 ± 1.68 h, t(½) 4.19 ± 1.81 and 7.65 ± 7.96 h, and mean AUC(last) 33.63 ± 20.41 and 32.50 ± 18.79 ng·h/mL. Higher AUC(last) and AUC from time zero to infinity (AUC(∞)), and lower apparent total body clearance of drug from plasma after oral administration (CL/F) for total ezetimibe and free ezetimibe were observed in female subjects compared with those in male subjects. There were no differences between the pharmacokinetic parameters of simvastatin and simvastatin acid for female and male subjects in the study.Ezetimibe/simvastatin combination tablet has a generally favourable safety and tolerability profile in healthy Chinese subjects. A statistically significant difference with regard to sex in the pharmacokinetics of ezetimibe was observed. Sex had no effect on the pharmacokinetics of simvastatin and simvastatin acid.