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Physiologically based pharmacokinetic modelling and in vivo [I]/K(i) accurately predict P-glycoprotein-mediated drug-drug interactions with dabigatran etexilate. #128
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.
https://www.ncbi.nlm.nih.gov/pubmed/24283665
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.
© 2013 The British Pharmacological Society.
KEYWORDS: P-glycoprotein; dabigatran etexilate; digoxin; physiologically based pharmacokinetic modelling; ‘in vivo’ Ki
PMID: 24283665 PMCID: PMC3925042 DOI: 10.1111/bph.12533