A2 IN VITRO TO IN VIVO TRANSLATION OF OATP-MEDIATED DRUG-DRUG INTERACTIONS IN CYNOMOLGUS MONKEY

Ayşe Ufuk , Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom
Rachel E. Kosa , Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT
Hongying Gao , Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT
Yi-An Bi , Pharmacokinetics, Dynamics and Metabolism Department, Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT
Sweta Modi , Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT
A. David Rodrigues , Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT
Larry Tremaine , Pharmacokinetics, Pharmacodynamics and Metabolism, Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT
Manthena V Varma , Department of Pharmacokinetics, Dynamics & Metabolism, Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT
J Brian Houston , Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom
Aleksandra Galetin , Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, United Kingdom
IN VITRO TO IN VIVO TRANSLATION OF OATP-MEDIATED DRUG-DRUG INTERACTIONS IN CYNOMOLGUS MONKEY

Ayşe Ufuk1, Rachel E. Kosa2, Hongying Gao2, Yi-an Bi2, Sweta Modi2, A. David Rodrigues2, Larry Tremaine2, Manthena Varma2, J. Brian Houston1 and Aleksandra Galetin1

1Centre for Applied Pharmacokinetic Research, University of Manchester, Manchester, UK; 2Pharmacokinetics, Dynamics and Metabolism, Medicine Design, Pfizer Worldwide R&D, Groton, CT

Organic anion transporting polypeptides (OATPs) are one of the most clinically relevant transporters associated with significant drug-drug interactions (DDIs) and safety concerns. Given that OATPs in cynomolgus monkey share a high degree of gene and amino acid sequence identity with human orthologs, we evaluated the in vitro – in vivo translation of OATP-mediated DDI risk using this preclinical model. Hepatic uptake of clinical probes, pitavastatin and rosuvastatin, was investigated in plated cynomolgus hepatocytes. In addition to kinetic studies, inhibition of OATPs was evaluated using rifampicin (0.01-100 µM) after 1h pre-incubation with either buffer or inhibitor. Intravenous pharmacokinetics of 2H4-pitavastatin and 2H6-rosuvastatin (0.2 mg/kg) and the oral pharmacokinetics of cold probes (0.2 mg/kg) were studied in cynomolgus monkeys (n=4) without or with co-administration of single oral ascending doses of rifampicin (1mg, 3mg, 10mg and 30mg). In vitro studies indicated >80% contribution of the active process to the total uptake and high affinity of pitavastatin and rosuvastatin for OATPs, with Km values of 2 µM and 3.9 µM, respectively. Rifampicin inhibited OATP-mediated uptake of pitavastatin and rosuvastatin in a concentration dependent manner with IC50 values of 3 and 0.54 µM, respectively following pre-incubation with the inhibitor. The pre-incubation step resulted in increased inhibition potency (2-fold) when rosuvastatin was used as a probe, whereas no shift in the IC50 was observed in the case of pitavastatin. A rifampicin dose-dependent reduction in intravenous clearance of OATP probes was observed, as pitavastatin and rosuvastatin clearance decreased to ~22% and ~45% of control, respectively, at rifampicin dose of 30 mg/kg. Oral pitavastatin and rosuvastatin plasma exposure also increased, with up to 19- and 15-fold change in AUC at the highest dose of rifampicin, respectively. Use of in vitro IC50 of 0.54 µM captured the change in mean intravenous clearance of statins as a function of mean unbound Cmax of rifampicin. In conclusion, this study demonstrates translation of rifampicin in vitro OATP IC50 to in vivo inhibition potency when using cynomolgus monkey as a preclinical species and may provide further confidence in application of in vitro human hepatocyte data for the prediction of clinical OATP-mediated DDIs.