Pharmacokinetics of dirlotapide in the dog.
An overview of the pharmacokinetics of dirlotapide in beagle dogs is presented. The following mean parameters were observed after a 0.3-mg/kg i.v. dose of dirlotapide: plasma clearance of 7.8 mL/min/kg and volume of distribution of 1.3 L/kg. Following single oral doses of 0.05, 0.3, and 1.0 mg/kg to fed dogs and 0.3 mg/kg to fasted dogs using the commercial formulation, mean C(max) of 7.5, 46, 97, and 31 ng/mL, respectively, were observed at mean t(max) of 0.8-2.0 h. AUC and C(max) increased with increasing dose, but not proportionally. Oral bioavailability was 22-41%. Exposure, as reflected by AUC, was 54% higher in the fed than fasted state. In a 14-day repeated-dose study (0.3 mg/kg dose), the mean accumulation ratio was 3.7. In a 3-month study at doses of 0.4-2.5 mg/kg, accumulation ratios ranged from 2.0 to 6.7 at day 29 and from 1.3 to 4.1 at day 87. In summary, dirlotapide exhibited low clearance, low first-pass metabolism, moderate volume of distribution, low-to-moderate oral bioavailability, a modest food effect, and variable accumulation. Large interanimal variability in systemic exposure was noted for all routes and doses, but there were no consistent sex differences.
Merritt
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Pfizer Animal Health, Veterinary Medicine Research & Development, Kalamazoo, MI 49001, USA. dawn.a.merritt@pfizer.com
Lynch
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King
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D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004285:Dogs / Q000378:metabolism*; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous / Q000662:veterinary; D008297:Male
D019440:Anti-Obesity Agents; D002219:Carbamates; D007211:Indoles; C521290:dirlotapide