Clinical Pharmacology

Mechanism of Action

Oclacitinib inhibits the function of a variety of pruritogenic cytokines and pro-inflammatory cytokines, as well as cytokines involved in allergy that are dependent on JAK1 or JAK3 enzyme activity. It has little effect on cytokines involved in hematopoiesis that are dependent on JAK2. Oclacitinib is not a corticosteroid or an antihistamine.

Pharmacokinetics

In dogs, oclacitinib maleate is rapidly and well absorbed following oral administration, with mean time to peak plasma concentrations (Tmax ) of less than 1 hour. Following oral administration of 0.4-0.6 mg oclacitinib/kg to 24 dogs, the mean (90% confidence limits [CL]) maximum concentration (Cmax ) was 324 (281, 372) ng/mL and the mean area under the plasma concentration-time curve from 0 and extrapolated to infinity (AUC0-inf ) was 1890 (1690, 2110) ng•hr/mL. The prandial state of dogs does not significantly affect the rate or extent of absorption. The absolute bioavailability of oclacitinib maleate was 89%.

Oclacitinib has low protein binding with 66.3-69.7% bound in fortified canine plasma at nominal concentrations ranging from 10-1000 ng/mL. The apparent mean (95% CL) volume of distribution at steady-state was 942 (870, 1014) mL/kg body weight.

Oclacitinib is metabolized in the dog to multiple metabolites and one major oxidative metabolite was identified in plasma and urine. Overall the major clearance route is metabolism with minor contributions from renal and biliary elimination. Inhibition of canine cytochrome P450 enzymes by oclacitinib is minimal; the inhibitory concentrations (IC50s ) are 50 fold greater than the observed Cmax values at the use dose.

Mean (95% CL) total body oclacitinib clearance from plasma was low - 316 (237, 396) mL/h/kg body weight (5.3 mL/min/kg body weight). Following IV and PO administration, the terminal t1/2 appeared similar with mean values of 3.5 (2.2, 4.7) and 4.1 (3.1, 5.2) hours, respectively.