Physiologically based pharmacokinetic modelling and in vivo [I]/K(i) accurately predict P-glycoprotein-mediated drug-drug interactions with dabigatran etexilate

Br J Pharmacol. 2014 Feb;171(4):1043-53. doi: 10.1111/bph.12533.

Abstract

Background and purpose: In vitro inhibitory potency (Ki )-based predictions of P-glycoprotein (P-gp)-mediated drug-drug interactions (DDIs) are hampered by the substantial variability in inhibitory potency. In this study, in vivo-based [I]/Ki values were used to predict the DDI risks of a P-gp substrate dabigatran etexilate (DABE) using physiologically based pharmacokinetic (PBPK) modelling.

Experimental approach: A baseline PBPK model was established with digoxin, a known P-gp substrate. The Km (P-gp transport) of digoxin in the baseline PBPK model was adjusted to Km (i) to fit the change of digoxin pharmacokinetics in the presence of a P-gp inhibitor. Then 'in vivo' [I]/Ki of this P-gp inhibitor was calculated using Km (i) /Km . Baseline PBPK model was developed for DABE, and the 'in vivo' [I]/Ki was incorporated into this model to simulate the static effect of P-gp inhibitor on DABE pharmacokinetics. This approach was verified by comparing the observed and the simulated DABE pharmacokinetics in the presence of five different P-gp inhibitors.

Key results: This approach accurately predicted the effects of five P-gp inhibitors on DABE pharmacokinetics (98-133% and 89-104% for the ratios of AUC and Cmax respectively). The effects of 16 other P-gp inhibitors on the pharmacokinetics of DABE were also confidently simulated.

Conclusions and implications: 'In vivo' [I]/Ki and PBPK modelling, used in combination, can accurately predict P-gp-mediated DDIs. The described framework provides a mechanistic basis for the proper design of clinical DDI studies, as well as avoiding unnecessary clinical DDI studies.

Keywords: P-glycoprotein; dabigatran etexilate; digoxin; physiologically based pharmacokinetic modelling; ‘in vivo’ Ki.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Amiodarone / analogs & derivatives
  • Amiodarone / pharmacology
  • Benzimidazoles / blood
  • Benzimidazoles / pharmacokinetics*
  • Clarithromycin / pharmacology
  • Dabigatran
  • Digoxin / blood
  • Digoxin / pharmacokinetics
  • Dronedarone
  • Drug Interactions
  • Humans
  • Models, Biological*
  • Pyridines / blood
  • Pyridines / pharmacokinetics*
  • Quinidine / pharmacology
  • Verapamil / pharmacology
  • beta-Alanine / analogs & derivatives
  • beta-Alanine / blood

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Benzimidazoles
  • Pyridines
  • beta-Alanine
  • Digoxin
  • Verapamil
  • Clarithromycin
  • Dabigatran
  • Quinidine
  • Dronedarone
  • Amiodarone