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

PI3Kα inhibitors are effective anticancer agents but are limited by hyperglycemic side effects that conventional hypoglycemic agents do not adequately control. This study investigated the pharmacokinetics and drug-drug interaction potential of dorzagliatin, a glucokinase activator approved in China for hyperglycemia, when combined with the PI3Kα inhibitors BYL719 and WX390 in a mouse tumor model, with plasma concentrations measured by LC-MS/MS and pharmacokinetic/pharmacodynamic parameters modeled using Phoenix WinNonlin. Co-administration increased dorzagliatin exposure (AUC increased 20-42%, Cmax increased 13-33%) while having minimal effect on PI3K inhibitor plasma exposure, and the combination of dorzagliatin with BYL719 showed superior antitumor efficacy compared with BYL719 monotherapy. The authors attribute the interaction partly to P-glycoprotein inhibition and suggest dorzagliatin’s insulin-regulating mechanism may help manage PI3K inhibitor-induced hyperglycemia while potentially enhancing antitumor activity.