A Mechanistic Framework for In Vitro–In Vivo Extrapolation of Liver Membrane Transporters: Prediction of Drug–Drug Interaction Between Rosuvastatin and Cyclosporine

Abstract

Background and ObjectivesThe interplay between liver metabolising enzymes and transporters is a complex process involving system-related parameters such as liver blood perfusion as well as drug attributes including protein and lipid binding, ionisation, relative magnitude of passive and active permeation. Metabolism- and/or transporter-mediated drug–drug interactions (mDDIs and tDDIs) add to the complexity of this interplay. Thus, gaining meaningful insight into the impact of each element on the disposition of a drug and accurately predicting drug–drug interactions becomes very challenging. To address this, an in vitro–in vivo extrapolation (IVIVE)-linked mechanistic physiologically based pharmacokinetic (PBPK) framework for modelling liver transporters and their interplay with liver metabolising enzymes has been developed and implemented within the Simcyp Simulator®.MethodsIn this article an IVIVE technique for liver transporters is described and a full-body PBPK model is developed. Passive and active (saturable) transport at both liver sinusoidal and canalicular membranes are accounted for and the impact of binding and ionisation processes is considered. The model also accommodates tDDIs involving inhibition of multiple transporters. Integrating prior in vitro information on the metabolism and transporter kinetics of rosuvastatin (organic-anion transporting polypeptides OATP1B1, OAT1B3 and OATP2B1, sodium-dependent taurocholate co-transporting polypeptide [NTCP] and breast cancer resistance protein [BCRP]) with one clinical dataset, the PBPK model was used to simulate the drug disposition of rosuvastatin for 11 reported studies that had not been used for development of the rosuvastatin model.ResultsThe simulated area under the plasma concentration–time curve (AUC), maximum concentration (Cmax) and the time to reach Cmax (tmax) values of rosuvastatin over the dose range of 10–80 mg, were within 2-fold of the observed data. Subsequently, the validated model was used to investigate the impact of coadministration of cyclosporine (ciclosporin), an inhibitor of OATPs, BCRP and NTCP, on the exposure of rosuvastatin in healthy volunteers.ConclusionThe results show the utility of the model to integrate a wide range of in vitro and in vivo data and simulate the outcome of clinical studies, with implications for their design.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-013-0097-y) contains supplementary material, which is available to authorized users.

The Antimicrobial Agent Fusidic Acid Inhibits Organic Anion Transporting Polypeptide-Mediated Hepatic Clearance and May Potentiate Statin-Induced Myopathy

“…These transporters are also expressed on the apical membrane of the enterocytes and are known to limit the intestinal absorption of several statins (Shitara et al, 2013). Inhibition of intestinal and/or biliary efflux (in addition to OATP inhibition) by cyclosporine A has been speculated as a potential factor for clinical DDIs with rosuvastatin, which is not susceptible to P450 metabolism (Jamei et al, 2014). In our studies, virtually no inhibitory effect (IC 50 .…”

Mixed–effects analysis of increased rosuvastatin absorption by coadministered telmisartan

“…[13] Two separate absorption rate constants (K a1 and K a2 ) were also used to fit the altered absorption profile in telmisartan coadministration group. There are mechanistic approaches such as physiologically based PK (PBPK) modeling using specialized software (Simcyp, Gatroplus, and PKsim) [14][15][16] and reduced (or simplified) PBPK modeling using NONMEM. [17,18] Rosuvastatin is a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, OATP2B1, and NTCP) and efflux transporters such as BCRP, and there are many clinically meaningful DDI data.…”

“…[17,18] Rosuvastatin is a substrate of hepatic uptake transporters (OATP1B1, OATP1B3, OATP2B1, and NTCP) and efflux transporters such as BCRP, and there are many clinically meaningful DDI data. [15,19,20] Telmisartan is an inhibitor of MRP, BCRP in in vitro, [21] but, as yet, there is no reported case of clinical transporter-mediated DDI of telmisartan as a perpetrator. In our final model, telmisartan affects the absorption process of rosuvastatin rather than its metabolic elimination.…”

“…[4] Rosuvastatin is extensively distributed into the liver, presumably because of active uptake by organicanion transporting polypeptides (OATPs)1B1, OATP1B3, and OATP2B1, and by the sodium-dependent taurocholated cotransporting polypeptide (NTCP) transporters, [5][6][7] despite its low passive diffusion into hepatocytes. [3,8,9] It is also a substrate of efflux transporters such as the liver canalicular and intestinal breast cancer resistance protein (BCRP). [10] Among patients with cardiovascular disease in a three-year retrospective study, 30.7% were found to have both hypertension and dyslipidemia, and 66.3% of patients with diabetes had concomitant hypertension and dyslipidemia.…”

Characterization of Contributing Factors to Variability in Morphine Clearance Through PBPK Modeling Implemented With OCT1 Transporter

“…and Rodgers and Rowland20 was used in the simulations. The permeability‐limited liver model was used to describe the liver distribution process 21, 22…”