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Projection of doses for QT‐prolongation studies based on modeling of the worst‐case inhibition of CYP3A
Author(s) -
Chien J. Y.,
Hall S. D.,
Wrighton S. A.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.12.012
Subject(s) - pharmacokinetics , bioavailability , pharmacology , cyp3a , clearance , dosing , ketoconazole , drug , medicine , distribution (mathematics) , quantile , qt interval , chemistry , urology , mathematics , statistics , antifungal , mathematical analysis , cytochrome p450 , dermatology , metabolism
Aims To project the probability of “worst‐case scenario” for CYP3A‐mediated ketoconazole (K) inhibition of CYP3A drugs based on modeling of pharmacokinetic inhibition effect to select doses for high‐dose QT prolongation studies for a low extraction ratio (ER) Drug A (range: 0.01–0.03) and high ER Drug B (range: 0.5–1). Both of these drugs are orally absorbed and cleared by CYP3A by unknown fractions (fm). Methods The predicted K portal vein and systemic concentration were used to drive its inhibitory effect on intrinsic clearance and bioavailability of Drugs A and B. Simulations were performed to test worst‐case scenarios, including the duration of K dosing and the range of drug's fm and ER. Results Performance of the model was assessed by comparing simulated trials to actual clinical trial results for A and B given with 200 mg K. The model well predicted the 2‐fold (A) and 6‐fold (B) AUC increases observed in the trials. Assuming worst‐case fm and bioavailability, 400 mg K produced less than doubling of AUC compared to results at 200 mg K for both drugs; maximum inhibition was obtained following 3 daily K doses. Doses for QT studies were then selected to achieve the 90 th or the 50 th quantile of the distribution of AUC ratios, or a 4‐ and 8‐fold exposure‐multiple from the target clinical doses, for Drugs A and B, respectively. Conclusions Model‐based projection of the probable worst‐case CYP3A inhibition can be used for high‐dose QT prolongation study design. Clinical Pharmacology & Therapeutics (2005) 77 , P31–P31; doi: 10.1016/j.clpt.2004.12.012