title: Development of a predictive pharmacokinetic model for a novel cyclooxygenase-2 inhibitor.
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.
authors.affiliation: Pharsight Corp, Mountain View, California, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kastrissios
authors.forename: S
authors.initials: S
authors.lastname: Rohatagi
authors.forename: J
authors.initials: J
authors.lastname: Moberly
authors.forename: K
authors.initials: K
authors.lastname: Truitt
authors.forename: Y
authors.initials: Y
authors.lastname: Gao
authors.forename: R
authors.initials: R
authors.lastname: Wada
authors.forename: M
authors.initials: M
authors.lastname: Takahashi
authors.forename: K
authors.initials: K
authors.lastname: Kawabata
authors.forename: D
authors.initials: D
authors.lastname: Salazar
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D044466:Asian People / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D008954:Models, Biological; D010641:Phenotype; D011758:Pyrroles / Q000097:blood / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011758:Pyrroles; D013449:Sulfonamides; C514354:apricoxib; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D019389:Cytochrome P-450 CYP2D6