title: The pharmacokinetics of mavacoxib, a long-acting COX-2 inhibitor, in young adult laboratory dogs.
abstract: The pharmacokinetics of mavacoxib were evaluated in an absolute bioavailability study, a dose-proportionality study and a multi-dose study in young healthy adult laboratory Beagle dogs and in a multi-dose safety study in Beagle-sized laboratory Mongrel dogs. When administered as the commercial tablet formulation at 4 mg/kg body weight (bw) to fasted dogs, the absolute bioavailability (F) of mavacoxib was 46.1%; F increased to 87.4% when mavacoxib was administered with food. Following intravenous administration, the total body plasma clearance of mavacoxib was 2.7 mL·h/kg, and the apparent volume of distribution at steady-state was 1.6 L/kg. The plasma protein binding of mavacoxib was approximately 98% in various in vitro and ex vivo studies. The dose-normalized area under the plasma concentration-time curve was similar in Beagle and Beagle-sized Mongrel dogs when mavacoxib was administered with food. Mavacoxib exhibited dose-proportional pharmacokinetics for single oral doses of 2-12 mg/kg in Beagle dogs and for multiple oral doses of 5-25 mg/kg in Beagle-sized Mongrel dogs. Only minor accumulation occurred when mavacoxib was administered at doses of 2-25 mg/kg bw orally to laboratory dogs with a 2-week interval between the 1st two doses but with a monthly interval thereafter. Across all three Beagle studies (n = 63) the median terminal elimination half-life (t(½) ) was 16.6 days, with individual values ranging 7.9-38.8 days. The prolonged t(½) for mavacoxib supports the approved regimen in which doses are separated by 2-4 weeks.
authors.affiliation: Veterinary Medicine Research and Development, Pfizer Inc., Kalamazoo, MI 49001-0199, USA. steven.r.cox@pfizer.com
authors.forename: S R
authors.initials: SR
authors.lastname: Cox
authors.forename: S P
authors.initials: SP
authors.lastname: Lesman
authors.forename: J F
authors.initials: JF
authors.lastname: Boucher
authors.forename: M J
authors.initials: MJ
authors.lastname: Krautmann
authors.forename: B D
authors.initials: BD
authors.lastname: Hummel
authors.forename: M
authors.initials: M
authors.lastname: Savides
authors.forename: S
authors.initials: S
authors.lastname: Marsh
authors.forename: A
authors.initials: A
authors.lastname: Fielder
authors.forename: M R
authors.initials: MR
authors.lastname: Stegemann
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D004285:Dogs / Q000097:blood* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D008297:Male; D011720:Pyrazoles / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D013237:Stereoisomerism; D000096926:Benzenesulfonamides
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011720:Pyrazoles; C555097:4-(5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides