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

• Published in: Journal of clinical pharmacology Vol. 46; no. 5; p. 537
• Main Authors: Kastrissios, H, Rohatagi, S, Moberly, J, Truitt, K, Gao, Y, Wada, R, Takahashi, M, Kawabata, K, Salazar, D
• Format: Journal Article
• Language: English
• Published: England 01.05.2006
• Subjects: Adult; Aryl Hydrocarbon Hydroxylases - genetics; Asian Continental Ancestry Group - genetics; Cyclooxygenase 2 Inhibitors - blood; Cyclooxygenase 2 Inhibitors - pharmacokinetics; Cytochrome P-450 CYP2C19; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2D6 - genetics; Double-Blind Method; Female; Humans; Male; Middle Aged; Mixed Function Oxygenases - genetics; Models, Biological; Phenotype; Pyrroles - blood; Pyrroles - pharmacokinetics; Sulfonamides - blood; Sulfonamides - pharmacokinetics
• ISSN: 0091-2700
• DOI: 10.1177/0091270006287122

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.