Development of a Physiologically Based Pharmacokinetic Model to Evaluate Dosing Regimens of Cyclosporine as a Precipitant of Organic Anion Transporting Polypeptide 1B (OATP1B)- and CYP3A4-Mediated Drug-Drug Interactions.

Cyclosporine (cyclosporin A or CsA), a clinically relevant but nonspecific inhibitor of hepatic organic anion transporting polypeptides (OATPs), is used for assessing transporter-mediated drug-drug interactions (DDIs) at varying dosing regimens. We developed a physiologically based pharmacokinetic model to reproduce CsA pharmacokinetics (PK) and effect of CsA on substrates of OATPs and cytochrome P450 (CYP)3A4. The model was built using intravenous and oral CsA clinical PK and DDI data in healthy volunteers. The model reproduces single- and multiple-dose clinical CsA PK from numerous studies with simulated/observed AUC and C_max within 0.59-1.75 following oral CsA dosing. As an object of CYP3A4, the model reproduces the observed effect of ketoconazole and grapefruit juice on CsA PK. CsA inhibition constants against CYP3A4 and hepatic OATPs were estimated to reproduce clinical DDIs with CYP3A index substrate midazolam (MDZ) and OATP1B biomarker coproporphyrin-I, and confirmed with felodipine and pitavastatin, verifying the model for inhibition of hepatic CYP3A4 and OATPs in healthy volunteers. A review of clinical data herein indicates that most clinical DDI studies utilize a single dose of CsA and for certain clinical substrates, a counterintuitive decrease in half-life following CsA administration has been observed (similar to single-dose rifampin DDIs). Using the currently developed CsA model, we predicted the effect of various single- and multiple-dose CsA regimens against OATP1B substrate and MDZ models. Depending on the OATP1B substrate characteristics, 200 mg CsA twice daily or a single 600 mg dose reasonably mimic simulated continuous OATP1B inhibition and single-dose rifampin, albeit with predicted weak-to-moderate CYP3A4 inhibition.