In vitro–in vivo extrapolation of OATP1B-mediated drug–drug interactions in cynomolgus monkey

Research output: Contribution to journalArticle

  • External authors:
  • Rachel E. Kosa
  • Hongying Gao
  • Yi An Bi
  • Sweta Modi
  • Dana Gates
  • A. David Rodrigues
  • Larry M. Tremaine
  • Manthena V.S. Varma

Abstract

Hepatic organic anion-transporting polypeptides (OATP) 1B1 and 1B3 are clinically relevant transporters associated with significant drug–drug interactions (DDIs) and safety concerns. Given that OATP1Bs in cynomolgus monkey share .90% degree of gene and amino acid sequence homology with human orthologs, we evaluated the in vitro–in vivo translation of OATP1B-mediated DDI risk using this preclinical model. In vitro studies using plated cynomolgus monkey hepatocytes showed active uptake Km values of 2.0 and 3.9 mM for OATP1B probe substrates, pitavastatin and rosuvastatin, respectively. Rifampicin inhibited pitavastatin and rosuvastatin active uptake in monkey hepatocytes with IC50 values of 3.0 and 0.54 mM, respectively, following preincubation with the inhibitor. Intravenous pharmacokinetics of 2H4-pitavastatin and 2H6-rosuvastatin (0.2 mg/kg) and the oral pharmacokinetics of cold probes (2 mg/kg) were studied in cynomolgus monkeys (n 5 4) without or with coadministration of single oral ascending doses of rifampicin (1, 3, 10, and 30 mg/kg). A rifampicin dose-dependent reduction in i.v. clearance of statins was observed. Additionally, oral pitavastatin and rosuvastatin plasma exposure increased up to 19- and 15-fold at the highest dose of rifampicin, respectively. Use of in vitro IC50 obtained following 1 hour preincubation with rifampicin (0.54 mM) predicted correctly the change in mean i.v. clearance and oral exposure of statins as a function of mean unbound maximum plasma concentration of rifampicin. This study demonstrates quantitative translation of in vitro OATP1B IC50 to predict DDIs using cynomolgus monkey as a preclinical model and provides further confidence in application of in vitro hepatocyte data for the prediction of clinical OATP1B-mediated DDIs.

Bibliographical metadata

Original languageEnglish
Pages (from-to)688-699
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Volume365
Issue number3
Early online date14 May 2018
DOIs
StatePublished - 1 Jun 2018