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FDA study demonstrates power of simulations in determining dosing strategies for DDI studies
Date: 27 Feb 2009
A new paper, entitled ‘Quantitative evaluation of pharmacokinetic inhibition of CYP3A substrates by ketoconazole – a simulation study’, has been published in the March edition of the Journal of Clinical Pharmacology. The study was undertaken by Ping Zhao and colleagues at the US Food and Drug Administration (FDA) in collaboration with prominent scientists from the University of Washington.
Draft drug interaction guidance from the FDA recommends an in vivo interaction study with a strong CYP3A inhibitor such as ketoconazole if in vitro studies indicate that a drug is a CYP3A substrate. The guidance indicates that once daily ketoconazole doses administered over several days will provide maximal CYP3A inhibition.
However, in response to reports suggesting that a single ketoconazole dose (400 mg) may be sufficient to elucidate clear inhibition of a CYP3A substrate, researchers at the FDA used in silico simulations to determine the impact of different inhibitor dosing regimens on AUC for theoretical substrates with various half-lives and bioavailability values.
The simulations indicate that the single dosing approach may be acceptable in some studies, however, only results in maximal inhibition for substrates with low bioavailability and short half-life values. For substrates with half-lives which exceed that of ketoconazole, multiple dosing of the inhibitor is critical and a 200mg twice daily dosing regimen resulted in more inhibition than once daily dosing at 400mg. Furthermore, the timing of ketoconazole administration must be optimised to achieve maximal CYP3A inhibition prior to administration of the substrate.
The authors highlight the importance of considering the pharmacokinetic characteristics of both substrate and inhibitor when designing an in vivo drug-drug interaction (DDI) study investigating CYP3A inhibition.
The Simcyp Population-based ADME Simulator (Version 8) was used throughout this study. To link to the abstract and full text options please click here.
The same edition of the journal features a letter to the editor written by Drs Oo and Chen from Asubio Pharmaceuticals. They outline the issue at the heart of the FDA study, proposing that single ketoconazole dosing should be considered as a practical alternative to existing guidelines.
A second letter is a response from the FDA written by Drs Shiew-Mei Huang and Lawrence J. Lesko. They urge study sponsors to recognise that there is no single optimal design for drug interaction evaluation and encourage the use of modelling and simulation to determine the best dosing strategy.