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Development of a Predictive Pharmacokinetic Model for a Novel Cyclooxygenase-2 Inhibitor

From Pharsight Corp, Mountain View, California (Dr Kastrissios, Dr Gao, Dr Wada), Sankyo Pharma Development, Edison, New Jersey (Dr Rohatagi, Dr Moberly, Dr Truitt, Dr Salazar), and Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd., Tokyo (Dr Takahashi, Dr Kawabata).

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.

Key Words: COX-2 inhibitors • population pharmacokinetics • genotyping

Address for reprints: S. Rohatagi, PhD, Clinical Pharmacology & Pharmacokinetics, Sankyo Pharma Development, 399 Thornall Street 11th Floor, Edison, NJ 08837; e-mail: srohatagi{at}sankyopharma.com.

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				S. Rohatagi, H. Kastrissios, Y. Gao, N. Zhang, J. Xu, J. Moberly, R. Wada, K. Yoshihara, M. Takahashi, K. Truitt, et al. Predictive Population Pharmacokinetic/Pharmacodynamic Model for a Novel COX-2 Inhibitor J. Clin. Pharmacol., March 1, 2007; 47(3): 358 - 370. [Abstract] [Full Text] [PDF]