A Clinical Cassette Dosing Study for Evaluating the Contribution of Hepatic OATPs and CYP3A to Drug-Drug Interactions

Abstract

The DDI study clarified the rate-determining processes of OATP/CYP3A substrates. Our analyses provide valuable information for predicting complex drug-drug interactions involving multiple processes.

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 .…”

“…The clinical DDI data were from the reports that investigated the impact of single or repeated dosing of rifampicin on the pharmacokinetics of repaglinide. [20][21][22][23][24] Our PBPK model incorporated the components for induction of OATP1B/CYP2C8/CYP3A and inhibition of OATP1B by rifampicin (Figure 5a,b, filled symbols). The parameters of repaglinide were first estimated using the blood repaglinide concentrationtime profiles under control condition (Table S2).…”

“…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.…”