Clarification of the Mechanism of Clopidogrel-Mediated Drug-Drug Interaction in a Clinical Cassette Small-dose Study and Its Prediction Based on In Vitro Information

Abstract

Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrelmediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model. Clopidogrel increased the AUC of pioglitazone (2.0-fold) and repaglinide (3.1-fold) but did not significantly change the AUC of pitavastatin (1.1-fold). In addition, the AUC of pioglitazone M4, a CYP2C8-mediated metabolite of pioglitazone, was reduced to 70% of the control by coadministration of clopidogrel. The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-b-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1). In conclusion, a single 300 mg of clopidogrel mainly inhibits CYP2C8-mediated metabolism by clopidogrel acylb-glucuronide, but its effect on the pharmacokinetics of OATP1B1 substrates is negligible. Clopidogrel is expected to have an effect not only on CYP2C8 substrates, but also dual CYP2C8/OATP1B1 substrates as seen in the case of repaglinide.

Expanded Physiologically‐Based Pharmacokinetic Model of Rifampicin for Predicting Interactions With Drugs and an Endogenous Biomarker via Complex Mechanisms Including Organic Anion Transporting Polypeptide 1B Induction

“…The parameters of repaglinide were first estimated using the blood repaglinide concentration‐time profiles under control condition ( Table ). When repaglinide was orally administered simultaneously with a single oral dose of 600 mg rifampicin, the predicted AUCRs (2.35–2.54) of repaglinide were within twofold of the observed AUCRs (1.92 ± 1.09 and 2.60 ± 1.49) regardless of the β values of repaglinide ( Figure b , left two boxes, filled symbols). In the case of repeated oral dosing of 600 mg rifampicin followed by an oral repaglinide dose simultaneously or 1–24 hours after the last rifampicin dose, the predicted AUCRs of repaglinide are shown in Figure b (right four boxes, filled symbols).…”

“…The clinical DDI data were from the reports that investigated the impact of single or repeated dosing of rifampicin on the pharmacokinetics of repaglinide . Our PBPK model incorporated the components for induction of OATP1B/CYP2C8/CYP3A and inhibition of OATP1B by rifampicin ( Figure a,b , filled symbols).…”

“…The prediction results were also obtained using the PBPK models that omitted a single component (detailed in the inset table; shown in different colors). First and second boxes: repaglinide was orally dosed with a single oral dose of 600 mg rifampicin . Third, fourth, fifth, and sixth boxes: repaglinide was orally dosed simultaneously or 1–24 hours after the last dose of repeated oral dosing of 600 mg rifampicin once daily for 5 or 7 days .…”

“…By incorporating additional components for the induction of OATP1B and CYP2C8, the prediction accuracy of DDIs may be improved for a variety of victim drugs. In the cases of glibenclamide (a substrate of OATP1B, CYP2C9, and CYP3A) and repaglinide (a substrate of OATP1B, CYP2C8, and CYP3A), a single dose of 600 mg rifampicin resulted in the AUCRs of 2.3 (glibenclamide) and 1.9 and 2.8 (repaglinide) . In contrast, repeated dosing of 600 mg rifampicin resulted in the AUCRs of 0.37 and 0.78 (glibenclamide) and 0.2–0.68 (repaglinide) These data suggest that the dosing schedules/intervals of rifampicin are important in determining the magnitude of DDIs with the substrates of OATP1B and CYP isoforms.…”

Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel

“…In recent years, clopidogrel has been found to significantly increase the exposure to several CYP2C8 substrates, e.g., repaglinide, pioglitazone, and montelukast . The main mechanism of the aforementioned DDIs is the strong time‐dependent CYP2C8 inactivation by clopidogrel's phase II acyl‐ β ‐D‐glucuronide metabolite .…”