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New publication: FDA scientists investigate DDI evaluation using the POP-PK approach
Date: 01 Oct 2010
A paper entitled ‘Bioavailability considerations in evaluating drug-drug interactions using the population pharmacokinetic approach’ describes research undertaken by scientists from the US Food and Drug Administration (FDA), Center for Drug Evaluation and Research. The article is currently in press in the Journal of Clinical Pharmacology.
The study was undertaken as it is recognised that evaluating the mechanism and magnitude of drug-drug interactions (DDIs) is a critical aspect in the development of new molecular entities. The common practice is to evaluate DDIs using a POP-PK approach using concomitant medication (COMD) as a covariate in the model. This study investigated the suitability of independently applying COMD to bioavailability and clearance for a ketoconazole/midazolam interaction study by simulating outcomes in virtual healthy volunteers using the Simcyp Population-based Simulator.
The results "reasonably capture" the observed drug interaction described in the literature, and large population variability was reported in the virtual healthy volunteer population. The mechanistic PBPK model considered inhibitor effects in different drug metabolising organs in a time-dependent manner. There was a near ten-fold decrease in the clearance of midazolam and a dramatic increase in its bioavailability in the presence of ketoconazole. These effects were mediated by the inhibition of first-pass metabolism in the gut and liver.
The major conclusion was the need to consider inhibition at the level of pre-systemic metabolism when evaluating DDI using POP-PK analysis, especially for substrates undergoing a significant first pass effect. Based on their results, the authors recommend that mechanistic simulations, such as using PBPK in virtual populations, are performed prior to design and sample collection of POP-PK studies.
The paper was authored by Duan et al. Please click here for a link to the abstract and full text options.