Quantitative Analysis of Complex Drug-Drug Interactions Between Repaglinide and Cyclosporin A/Gemfibrozil Using Physiologically Based Pharmacokinetic Models With In Vitro Transporter/Enzyme Inhibition Data

J Pharm Sci. 2017 Sep;106(9):2715-2726. doi: 10.1016/j.xphs.2017.04.063. Epub 2017 May 4.

Abstract

Quantitative analysis of transporter- and enzyme-mediated complex drug-drug interactions (DDIs) is challenging. Repaglinide (RPG) is transported into the liver by OATP1B1 and then is metabolized by CYP2C8 and CYP3A4. The purpose of this study was to describe the complex DDIs of RPG quantitatively based on unified physiologically based pharmacokinetic (PBPK) models using in vitro Ki values for OATP1B1, CYP3A4, and CYP2C8. Cyclosporin A (CsA) or gemfibrozil (GEM) increased the blood concentrations of RPG. The time profiles of RPG and the inhibitors were analyzed by PBPK models, considering the inhibition of OATP1B1 and CYP3A4 by CsA or OATP1B1 inhibition by GEM and its glucuronide and the mechanism-based inhibition of CYP2C8 by GEM glucuronide. RPG-CsA interaction was closely predicted using a reported in vitro Ki,OATP1B1 value in the presence of CsA preincubation. RPG-GEM interaction was underestimated compared with observed data, but the simulation was improved with the increase of fm,CYP2C8. These results based on in vitro Ki values for transport and metabolism suggest the possibility of a bottom-up approach with in vitro inhibition data for the prediction of complex DDIs using unified PBPK models and in vitro fm value of a substrate for multiple enzymes should be considered carefully for the prediction.

Keywords: CYP enzymes; clinical trial simulations; drug interactions; organic anion-transporting polypeptide transporters; pharmacokinetics; physiologically based pharmacokinetic modeling.

MeSH terms

  • Biological Transport / drug effects
  • Carbamates / blood*
  • Carbamates / metabolism
  • Carbamates / pharmacology
  • Computer Simulation
  • Cyclosporine / pharmacology*
  • Cytochrome P-450 CYP2C8 / metabolism
  • Cytochrome P-450 CYP2C8 Inhibitors / pharmacology
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Gemfibrozil / pharmacology*
  • Humans
  • Hypoglycemic Agents / blood*
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacology
  • Liver-Specific Organic Anion Transporter 1 / metabolism
  • Models, Biological
  • Piperidines / blood*
  • Piperidines / metabolism
  • Piperidines / pharmacology

Substances

  • Carbamates
  • Cytochrome P-450 CYP2C8 Inhibitors
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Liver-Specific Organic Anion Transporter 1
  • Piperidines
  • SLCO1B1 protein, human
  • repaglinide
  • Cyclosporine
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Gemfibrozil