Physiologically ‐based Pharmacokinetic Predictions of Intestinal BCRP‐Mediated Effect of Telmisartan on the Pharmacokinetics of Rosuvastatin in Humans

Abstract It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan. The aim of this study was to explore the mechanism of the interaction of telmisartan and rosuvastatin. A full‐PBPK model of telmisartan was developed, and the rosuvastatin model in Simcyp (version 15)’s drug library was modified to reflect ethnic differences in rosuvastatin exposure. PK characteristics, including intestinal and hepatic transporter / enzyme specificities of telmisartan and rosuvastatin, were incorporated into the PBPK models to simulate a rosuvastatin (20 mg) – telmisartan (80 mg) multiple dose drug interaction study. The simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without telmisartan) ratios were 1.96 and 1.17, respectively, and the Tmax changed from 3.35 h to 1.41 h with coadministration of telmisartan, which are consistent with the aforementioned report (CmaxI/Cmax: 2.01, AUCI/AUC:1.18, Tmax: 5 h → 0.75 h). The decrease in the CLint,BCRP, intestine of rosuvastatin by telmisartan in the PBPK model was pivotal to reproducing this finding in Simcyp. Although most of the PK changes of rosuvastatin are known to be OATP1B1‐mediated, our PBPK model demonstrated that the major cause of rosuvastatin–telmisartan DDI is intestinal BCRP‐mediated, and not OATP1B1/1B3‐mediated interactions.
Source: Biopharmaceutics and Drug Disposition - Category: Drugs & Pharmacology Authors: Tags: Original Paper Source Type: research