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Pharmacokinetics, Safety and Tolerability of Chiglitazar, A Novel Peroxisome Proliferator-Activated Receptor (PPAR) Pan-Agonist, in Healthy Chinese Volunteers: A Phase I Study

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Abstract

Background and Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgements

The authors wish to thank the participants, study investigators, coordinators and study site personnel who contributed to this study.

Author information

Author notes

  1. Hong-Rong Xu and Jin-Wen Zhang were considered equally contributed to this work.

Authors and Affiliations

  1. Department of Clinical Pharmacology, ZhongShan Hospital, Fudan University, No. 180, Fenglin Road, Xuhui District, Shanghai, 200032, People’s Republic of China

    Hong-Rong Xu, Wei-li Chen & Xue-Ning Li

  2. Chipscreen Biosciences Co., Ltd., Bio-Incubator Suite 2-601, Shenzhen Hi-Tech Industrial Park, Nanshan District, Shenzhen, 518057, Guangdong, People’s Republic of China

    Jin-Wen Zhang & Zhi-Qiang Ning

Authors
  1. Hong-Rong Xu
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  2. Jin-Wen Zhang
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Contributions

All authors participated in the design of the study and contributed to acquisition, analysis and interpretation of data. The sponsor, Chipscreen Biosciences Co., Ltd, provided for editorial and medical writing support. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Xue-Ning Li.

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Conflict of Interest

Jin-Wen Zhang and Zhi-Qiang Ning are employees of Shenzhen Chipscreen Biosciences Co., Ltd. Hong-Rong Xu, Wei-Li Chen and Xue-Ning Li are employees of ZhongShan Hospital, Fudan University, and declare that they have no conflicts of interest in this study.

Funding

The study was supported by the following project Grants: (1) “Research on the pharmacokinetics of chiglitazar tablet, a new drug in category 1.1 for diabetes” (No. CXZZ20151013171242907) from the Shenzhen Science and Technology Innovation Committee; (2) a National Science and Technology “863” Project (No. 2002AA2Z3146); and (3) a National Science and Technology Significant Project in the category “New Drug Initiative” (2008ZX09101-002).

Ethical Approval

The study protocol was approved by the independent ethics committee and the institutional review board of the ZhongShan Hospital, Fudan University. The study was performed in accordance with the Declaration of Helsinki, the Good Clinical Practice Guidelines and local laws.

Informed Consent

Written informed consent was obtained from all individual participants prior to their enrolment.

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Xu, HR., Zhang, JW., Chen, Wl. et al. Pharmacokinetics, Safety and Tolerability of Chiglitazar, A Novel Peroxisome Proliferator-Activated Receptor (PPAR) Pan-Agonist, in Healthy Chinese Volunteers: A Phase I Study. Clin Drug Investig 39, 553–563 (2019). https://doi.org/10.1007/s40261-019-00779-4

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