Physiologically Based Pharmacokinetic Modeling of Rosuvastatin to Predict Transporter-Mediated Drug-Drug Interactions

Nina Hanke,Valerie Nock,Naoki Ishiguro,Peter Stopfer,José David Gómez-Mantilla

doi:10.1007/s11095-021-03109-6

Abstract

PurposeTo build a physiologically based pharmacokinetic (PBPK) model of the clinical OATP1B1/OATP1B3/BCRP victim drug rosuvastatin for the investigation and prediction of its transporter-mediated drug-drug interactions (DDIs).MethodsThe Rosuvastatin model was developed using the open-source PBPK software PK-Sim®, following a middle-out approach. 42 clinical studies (dosing range 0.002–80.0 mg), providing rosuvastatin plasma, urine and feces data, positron emission tomography (PET) measurements of tissue concentrations and 7 different rosuvastatin DDI studies with rifampicin, gemfibrozil and probenecid as the perpetrator drugs, were included to build and qualify the model.ResultsThe carefully developed and thoroughly evaluated model adequately describes the analyzed clinical data, including blood, liver, feces and urine measurements. The processes implemented to describe the rosuvastatin pharmacokinetics and DDIs are active uptake by OATP2B1, OATP1B1/OATP1B3 and OAT3, active efflux by BCRP and Pgp, metabolism by CYP2C9 and passive glomerular filtration. The available clinical rifampicin, gemfibrozil and probenecid DDI studies were modeled using in vitro inhibition constants without adjustments. The good prediction of DDIs was demonstrated by simulated rosuvastatin plasma profiles, DDI AUClast ratios (AUClast during DDI/AUClast without co-administration) and DDI Cmax ratios (Cmax during DDI/Cmax without co-administration), with all simulated DDI ratios within 1.6-fold of the observed values.ConclusionsA whole-body PBPK model of rosuvastatin was built and qualified for the prediction of rosuvastatin pharmacokinetics and transporter-mediated DDIs. The model is freely available in the Open Systems Pharmacology model repository, to support future investigations of rosuvastatin pharmacokinetics, rosuvastatin therapy and DDI studies during model-informed drug discovery and development (MID3).

Highlights

The most commonly recommended clinical substrates for the study of organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/OATP1B3) mediated drug-drug interactions (DDIs) are rosuvastatin, pravastatin and pitavastatin [1,2,3]
The objective of this study was to develop a wholebody physiologically based pharmacokinetic (PBPK) model of rosuvastatin to support the investigation of drug-drug interactions, that (i) reliably predicts the rosuvastatin concentrations in blood, liver, feces and urine, (ii) incorporates the most important transporters involved in rosuvastatin pharmacokinetics and drug-drug interactions and (iii) mechanistically describes the impact of the perpetrator drugs rifampicin, gemfibrozil and probenecid on the pharmacokinetics of rosuvastatin
To describe the pharmacokinetics of rosuvastatin, active transport by OATP2B1, OATP1B1/1B3, OAT3, Pgp and breast cancer resistance protein (BCRP) as well as metabolism by CYP2C9 were implemented into the model

Summary

Introduction

The most commonly recommended clinical substrates for the study of organic anion transporting polypeptide 1B1 and 1B3 (OATP1B1/OATP1B3) mediated drug-drug interactions (DDIs) are rosuvastatin, pravastatin and pitavastatin [1,2,3]. These drugs are substrates of OATP1B1 and OATP1B3, and of OATP2B1, breast cancer resistance protein (BCRP) and P-glycoprotein (Pgp) [1, 3]. Unspecific inhibitors (or inducers) that affect multiple transporters are routinely used, which complicates the interpretation of clinical DDI study results. Rosuvastatin has been shown to increase high-density lipoprotein (HDL) and to lower triglyceride concentrations in the blood [5]

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