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Physiologically based pharmacokinetics model predicts the lack of inhibition by repaglinide on the metabolism of pioglitazone

Purpose: Repaglinide and pioglitazone are both CYP2C8 and CYP3A4 substrates. This study was to determine whether repaglinide has an inhibitory effect on the metabolism of pioglitazone in vitro, in silico and in vivo. Method: In vitro, the effect of repaglinide on the metabolism of pioglitazone was assessed in pooled human liver microsomes. In silico, an IVIVE‐PBPK linked model was built with Simcyp®. Then, a randomized, 2‐phase cross‐over clinical study was conducted in 12 healthy volunteers. Results: Repaglinide showed a strong inhibitory effect on the metabolism of pioglitazone in vitro (Ki = 0.0757 µm), [I]/Ki > 0.1. The Simcyp® prediction ratios of AUC and Cmax between the two treatment groups were both about 1.01. The pharmacokinetics of pioglitazone in clinical trials showed no significant difference between these two treatment groups (p > 0.05). Conclusion: Repaglinide has no significant inhibitory effect on the metabolism of pioglitazone in vivo, which is inconsistent with the in vitro results. The lack of an inhibitory effect was partly due to extensive plasma protein binding and to the high in vivo clearance of repaglinide, for the concentration of repaglinide in vivo was far smaller than in vitro. Copyright © 2015 John Wiley & Sons, Ltd.