Abstract
Several reports in the literature present the utility and value of in vitro drug-metabolizing enzyme inhibition data to predict in vivo drug-drug interactions in humans. A retrospective analysis has been conducted for 26 GlaxoSmithKline (GSK) drugs and drug candidates for which in vitro inhibition parameters have been determined, and clinical drug interaction information, from a total of 46 studies, is available. The dataset, for drugs with a diverse range of physiochemical properties, included both reversible and potentially irreversible cytochrome P450 inhibitors for which in vitro inhibition parameters (IC50 or KI/kinact as appropriate) were determined using standardized methodologies. Mechanistic static models that differentiated reversible and metabolism-dependent inhibition, and also considered the contribution of intestinal metabolism for CYP3A4 substrates, were applied to estimate the magnitude of the interactions. Several pharmacokinetic parameters, including total Cmax, unbound Cmax, as well as estimates of hepatic inlet and liver concentration, were used as surrogates for the inhibitor concentration at the enzyme active site. The results suggest that estimated unbound liver concentration or unbound hepatic inlet concentration, with consideration of intestinal contribution, offered the most accurate predictions of drug-drug interactions (occurrence and magnitude) for the drugs in this dataset. When used with epidemiological information on comedication profiles for a given therapeutic area, these analyses offer a quantitative risk assessment strategy to inform the necessity of excluding specific comedications in early clinical studies and the ultimate requirement for clinical drug-drug interaction studies. This strategy has significantly reduced the number of clinical drug interaction studies performed at GSK.
Footnotes
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.111.039214.
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ABBREVIATIONS:
- DDI
- drug-drug interaction
- P450
- cytochrome P450
- fm
- fraction substrate eliminated by a single (P450) pathway
- Fg
- gut availability (fraction of absorbed substrate escaping gut metabolism)
- PK
- pharmacokinetics
- GSK
- GlaxoSmithKline
- BCS
- Biopharmaceutics Classification System
- AUC
- area under the plasma or blood concentration vs time curve
- HLM
- human liver microsomes
- KI
- concentration of inhibitor required to achieve half-maximal inactivation
- Ki
- inhibition constant
- kinact
- maximal rate constant of enzyme inactivation
- QWBA
- quantitative whole-body autoradiography
- ka
- absorption rate constant
- Fa
- fraction of dose absorbed
- D
- dose
- Qh
- liver blood flow
- [I]
- concentration of inhibitor available to enzyme
- Qg
- intestinal blood flow
- kdeg
- rate constant for enzyme degradation
- AUCi/AUC
- ratio of AUC in presence and absence of inhibitor
- TP
- true positive
- TN
- true negative
- FP
- false positive
- FN
- false negative
- AD
- average deviation
- RMSE
- root-mean-square error
- NCE
- new chemical entity
- PoC
- proof of concept.
- Received March 28, 2011.
- Accepted August 10, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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