Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method

Clin Pharmacol Ther. 2016 Nov;100(5):513-523. doi: 10.1002/cpt.391. Epub 2016 Jul 28.

Abstract

This study aimed to construct a widely applicable method for quantitative analyses of drug-drug interactions (DDIs) caused by the inhibition of hepatic organic anion transporting polypeptides (OATPs) using physiologically based pharmacokinetic (PBPK) modeling. Models were constructed for pitavastatin, fluvastatin, and pravastatin as substrates and cyclosporin A (CsA) and rifampicin (RIF) as inhibitors, where enterohepatic circulations (EHC) of statins were incorporated. By fitting to clinical data, parameters that described absorption, hepatic elimination, and EHC processes were optimized, and the extent of these DDIs was explained satisfactorily. Similar in vivo inhibition constant (Ki ) values of each inhibitor against OATPs were obtained, regardless of the substrates. Estimated Ki values of CsA were comparable to reported in vitro values with the preincubation of CsA, while those of RIF were smaller than reported in vitro values (coincubation). In conclusion, this study proposes a method to optimize in vivo PBPK parameters in hepatic uptake transporter-mediated DDIs.

MeSH terms

  • Antibiotics, Antitubercular / pharmacology
  • Computer Simulation
  • Cyclosporine / pharmacology
  • Drug Interactions
  • Enzyme Inhibitors / pharmacology*
  • Fatty Acids, Monounsaturated / blood
  • Fatty Acids, Monounsaturated / pharmacokinetics
  • Fluvastatin
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / blood
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacokinetics*
  • Indoles / blood
  • Indoles / pharmacokinetics
  • Liver / metabolism*
  • Models, Biological
  • Organic Anion Transporters / antagonists & inhibitors*
  • Organic Anion Transporters / metabolism*
  • Pravastatin / blood
  • Pravastatin / pharmacokinetics
  • Quinolines / blood
  • Quinolines / pharmacokinetics
  • Rifampin / pharmacology

Substances

  • Antibiotics, Antitubercular
  • Enzyme Inhibitors
  • Fatty Acids, Monounsaturated
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Indoles
  • Organic Anion Transporters
  • Quinolines
  • Fluvastatin
  • Cyclosporine
  • Pravastatin
  • pitavastatin
  • Rifampin