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Population Pharmacokinetic/Pharmacodynamic Analysis of the Glucokinase Activator PB201 in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus: Facilitating the Clinical Development of PB201 in China

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Abstract

PB201 is an orally active, partial glucokinase activator targeting both pancreatic and hepatic glucokinase. As the second glucokinase activator studied beyond phase I, PB201 has demonstrated promising glycemic effects as well as favorable pharmacokinetic (PK) and safety profiles in patients with type 2 diabetes mellitus (T2DM). This study aims to develop a population PK/pharmacodynamic (PD) model for PB201 using the pooled data from nine phase I/II clinical trials conducted in non-Chinese healthy volunteers and a T2DM population and to predict the PK/PD profile of PB201 in a Chinese T2DM population. We developed the PK/PD model using the non-linear mixed-effects modeling approach. All runs were performed using the first-order conditional estimation method with interaction. The pharmacokinetics of PB201 were well fitted by a one-compartment model with saturable absorption and linear elimination. The PD effects of PB201 on reducing the fasting plasma glucose and glycosylated hemoglobin levels in the T2DM population were described by indirect response models as stimulating the elimination of fasting plasma glucose, where the production of glycosylated hemoglobin was assumed to be stimulated by fasting plasma glucose. Covariate analyses revealed enhanced absorption of PB201 by food and decreased systemic clearance with ketoconazole co-administration, while no significant covariate was identified for the pharmacodynamics. The population PK model established for non-Chinese populations was shown to be applicable to the Chinese T2DM population as verified by the PK data from the Chinese phase I study. The final population PK/PD model predicted persistent and dose-dependent reductions in fasting plasma glucose and glycosylated hemoglobin levels in the Chinese T2DM population receiving 50/50 mg, 100/50 mg, and 100/100 mg PB201 twice daily for 24 weeks independent of co-administration of metformin. Overall, the proposed population PK/PD model quantitatively characterized the PK/PD properties of PB201 and the impact of covariates on its target populations, which allows the leveraging of extensive data in non-Chinese populations with the limited data in the Chinese T2DM population to successfully supported the waiver of the clinical phase II trial and facilitate the optimal dose regimen design of a pivotal phase III study of PB201 in China.

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Author notes

  1. Ling Song and Fangrui Cao equally contributed to this study.

Authors and Affiliations

  1. Drug Clinical Trial Center, Peking University Third Hospital, Beijing, 100191, China

    Ling Song, Fangrui Cao, Shu Niu, Xueting Yao & Dongyang Liu

  2. Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China

    Ling Song

  3. Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China

    Ling Song & Dongyang Liu

  4. PegBio Co., Ltd., Suzhou, Jiangsu, China

    Michael Xu, Ruifang Liang, Ke Ding & Zhigang Lin

  5. Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Third Hospital, Beijing, China

    Dongyang Liu

Authors
  1. Ling Song
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  3. Shu Niu
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  4. Michael Xu
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Corresponding authors

Correspondence to Xueting Yao or Dongyang Liu.

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Funding

The study was supported by the National Natural Science Foundation of China (no. 82173895 and no. 82373954), The Bill & Melinda Gates Foundation (Grant/Award Number: INV-007625) and the Peking University Third Hospital Clinical Project (Grant/Award Number: BYSYFY2021006).

Conflicts of interest/competing interests

Michael Xu, Ruifang Liang, Ke Ding, and Zhigang Lin are employees of PegBio Co., Ltd., (Suzhou, Jiangsu, China) the company that owns PB201. Ling Song, Fangrui Cao, and Dongyang Liu have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

The data used in this study were collected in line with the principles of the Declaration of Helsinki. Approval was granted by institutional review boards and independent ethics committees for each study of which data were used in this work.

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Not applicable.

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Not applicable.

Availability of data and material

All data generated or analyzed during this study are included in this published article (and its supplementary information files).

Code availability

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Authors’ contributions

LS, FC, and DL designed the study. LS and FC conducted the modeling and simulation work. MX, RL, KD, and ZL provided the clinical raw data.

Supplementary Information

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Supplementary file2 (DOCX 19073 KB)

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Song, L., Cao, F., Niu, S. et al. Population Pharmacokinetic/Pharmacodynamic Analysis of the Glucokinase Activator PB201 in Healthy Volunteers and Patients with Type 2 Diabetes Mellitus: Facilitating the Clinical Development of PB201 in China. Clin Pharmacokinet 63, 93–108 (2024). https://doi.org/10.1007/s40262-023-01321-8

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