In Vivo PK-PD and Drug-Drug Interaction Study of Dorzagliatin for the Management of PI3Kα Inhibitor-Induced Hyperglycemia

Guanqin Jin; Kewei Zheng; Shihuang Liu; Huan Yi; Wei Wei; Congjian Xu; Xiaoqiang Xiang; Yu Kang

doi:10.3390/ph18060927

In Vivo PK-PD and Drug-Drug Interaction Study of Dorzagliatin for the Management of PI3Kα Inhibitor-Induced Hyperglycemia

Pharmaceuticals (Basel). 2025 Jun 19;18(6):927. doi: 10.3390/ph18060927.

Authors

Guanqin Jin^{1

2

3}, Kewei Zheng^{2

3}, Shihuang Liu^{4

5}, Huan Yi^{4

5}, Wei Wei⁶, Congjian Xu^{2

3

7}, Xiaoqiang Xiang⁸, Yu Kang^{1

2

3}

Affiliations

¹ Clinical Research Center, Obstetrics & Gynecology Hospital of Fudan University, Shanghai 200433, China.
² Shanghai Key Lab of Female Reproductive Endocrine Related Diseases, Shanghai 200433, China.
³ Shanghai Key Lab of Reproduction and Development, Shanghai 200433, China.
⁴ Department of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou 350001, China.
⁵ Fujian Province Key Clinical Specialty for Gynecology, Fujian Key Laboratory of Women and Children's Critical Diseases Research, National Key Gynecology Clinical Specialty Construction Institution of China, Fuzhou 350001, China.
⁶ Department of Translational Medicine, Shanghai Jiatan Pharmatech Co., Ltd., Shanghai 201203, China.
⁷ Department of Obstetrics and Gynecology, Shanghai Medical School, Fudan University, Shanghai 200032, China.
⁸ Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai 201203, China.

Abstract

Objectives: The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Dorzagliatin, a novel glucokinase activator, has been approved in China for the management of hyperglycemia, offering a promising alternative. This study aims to investigate the pharmacokinetic properties and potential mechanisms of drug interactions of dorzagliatin in the regulation of PI3K-induced hyperglycemia. Methods: Plasma concentrations of WX390, BYL719, and Dorz in mice were measured using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic (PK) parameters and PK/PD models were derived by using Phoenix WinNonlin 8.3.5 software. Blood glucose levels at various time points and tumor volume changes over a four-week period were assessed to explore the interactions when PI3Ki were combined with dorzagliatin. Results: The results indicated that, compared to the Dorz group, the combination groups (Dorz + BYL719, Dorz + WX390) exhibited increases in AUC0→t of dorzagliatin by 41.65% and 20.25%, and in C_max by 33.48% and 13.32%, respectively. In contrast, co-administration of these PI3Ki with dorzagliatin resulted in minimal increase in their plasma exposure. The combination therapy group (Dorz+BYL719) exhibited superior antitumor efficacy compared to the BYL719 group. Conclusions: Our findings indicate that the drug-drug interactions (DDIs) between dorzagliatin and multiple PI3Ki (including WX390 and BYL719) may partially account for the enhanced antitumor efficacy observed in the combination therapy group compared to PI3Ki monotherapy. This interaction may be explained by the inhibition of P-glycoprotein (P-gp) and the pharmacological mechanism of dorzagliatin regarding the activation of insulin regulation.

Keywords: LC-MS/MS analysis; P-gp-mediated drug–drug interaction; PI3Kα inhibitors; PK/PD models; dorzagliatin.

Abstract

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