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Development of a Predictive Pharmacokinetic Model for a Novel Cyclooxygenase‐2 Inhibitor
Author(s) -
Kastrissios H.,
Rohatagi S.,
Moberly J.,
Truitt K.,
Gao Y.,
Wada R.,
Takahashi M.,
Kawabata K.,
Salazar D.
Publication year - 2006
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270006287122
Subject(s) - pharmacokinetics , bioavailability , cyclooxygenase , pharmacology , population , medicine , compartment (ship) , nonmem , chemistry , enzyme , biochemistry , oceanography , environmental health , geology
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.