Development of a predictive pharmacokinetic model for a novel cyclooxygenase-2 inhibitor

Journal of Clinical Pharmacology
H KastrissiosD Salazar

Abstract

A predictive population pharmacokinetic model was developed for a novel cyclooxygenase-2 (COX-2) inhibitor CS-706, using data from 130 subjects in 3 phase 1 trials after single or multiple doses of CS-706 (2- to 800-mg doses daily, up to 14 days) and validated using sparse data from a separate study. A 2-compartment model described the data. Typical apparent clearance (CL/F) was 47.2 L/h and was reduced by 43% at doses greater than 200 mg. Apparent clearance was decreased by 38% in female subjects and by 64% and 15%, respectively, in poor/intermediate CYP 2D6 and poor CYP 2C9 metabolizers. Typical apparent volume of the central compartment was 166 L and increased with body weight. Bioavailability increased by 42% after nighttime doses and decreased saturably with increasing dose (50% reduction at 221 mg). Predicted exposures in Japanese subjects were reduced relative to whites because of a lower frequency of poor metabolizers. The model may aid in optimizing the design of future studies and predicting exposures in other subpopulations.

References

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Dec 3, 1999·Journal of Clinical Pharmacy and Therapeutics·E Tanaka
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Sep 3, 2004·Journal of Clinical Pharmacology·Kiman KimHartmut Derendorf

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Citations

Oct 21, 2006·Journal of Pharmacokinetics and Pharmacodynamics·Stacey J TannenbaumDiane R Mould
Jun 5, 2008·British Journal of Clinical Pharmacology·Shashank RohatagiDaniel E Salazar
Feb 27, 2007·Journal of Clinical Pharmacology·S RohatagiD Salazar

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