Drug-Drug Interaction of Chiglitazar with Empagliflozin, Atorvastatin, and Valsartan: An Open-Label, Single-Center, Self-Control, 3-Period Study

Lei Sheng,1 Xuening Li,1 Jia Yu,2 Xiaodong Yang,2 Hui Li,1 Hongrong Xu1 1Department of Clinical Pharmacology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China; 2Department of Clinical Pharmacology, Shenzhen Chipscreen Biosciences Co., Ltd, Shenzhen, Guangdong, People’s Republic of ChinaCorrespondence: Hongrong Xu; Hui Li, Email [email protected]; [email protected] and Objectives: This study aimed to characterize the drug-drug interactions (DDIs) between chiglitazar and three commonly prescribed organic anion transporting polypeptides (OATP) 1B1/1B3 substrates (empagliflozin, atorvastatin, and valsartan) in healthy Chinese participants.Methods: In this Phase I study, healthy participants received a single oral dose of empagliflozin (10 mg), atorvastatin (20 mg), and valsartan (160 mg) on Day 1 and an oral dose of chiglitazar (48 mg) once daily from Day 5 to Day 9. On Day 10, participants received the last single dose of chiglitazar (48 mg), concurrently with a single dose of either empagliflozin (10 mg), atorvastatin (20 mg), or valsartan (160 mg). Pharmacokinetic (PK) parameters were calculated using non-compartmental analysis and the possible DDIs were statistically evaluated by mixed-effects models.Results: Chiglitazar exposure was not significantly changed when co-administrated with empagliflozin, atorvastatin, or valsartan. As a perpetrator of DDI, co-administration of chiglitazar had a minimal effect on empagliflozin exposure, whereas it decreased valsartan area under the concentration-time curve (AUC) from time 0 to infinity (AUC0-inf) by 14.3% and maximum observed plasma concentration (Cmax) by 24.7%, respectively. Although co-administration of chiglitazar decreased atorvastatin AUC0-inf by 26.6% and Cmax by 26.9%, respectively, it had no effect on its primary metabolite, 2-hydroxy atorvastatin, with its AUC0-inf and Cmax decreasing by only 7.7% and 1.2%, respectively. For atorvastatin and valsartan, the 90% confidence intervals (CIs) for AUC0-inf and Cmax extended below the 80% lower bioequivalence limit. Although the reductions were unexpected, they were not considered clinically significant based on the therapeutic contexts.Conclusion: Although the PK interactions of chiglitazar with atorvastatin and valsartan led to exposure reductions that fell outside the standard bioequivalence limits, these reductions were not expected to have clinical significance. Therefore, chiglitazar can be co-administered with these OATP1B1/1B3 substrates without dose adjustments.Clinical Trial Registration: NCT05681273 (ClinicalTrials.gov).Keywords: drug-drug interaction, pharmacokinetics, safety, chiglitazar, OATP