Single-dose pharmacokinetics and bioavailability of a novel extended duration transdermal buprenorphine solution in cats.

Abstract

A novel transdermal buprenorphine solution (TBS) was developed for evaluation in order to make available an extended duration opioid analgesic for cats. Healthy adult cats were administered a single TBS dose of 10mg (1.57-4.35mg/kg), 30mg (4.72-13.0mg/kg), or 50mg (7.87-21.7mg/kg) (4 cats per group) applied topically to the unclipped dorsal cervical skin and plasma buprenorphine concentrations were evaluated through 7days. To determine the absolute bioavailability of TBS, healthy cats were administered single TBS dose of 20mg (3.33-4.76mg/kg) or 0.05mg (0.008-0.011mg/kg) IV buprenorphine (6 cats per group). The mean±standard deviation maximum plasma buprenorphine concentrations (Cmax ) were 10.5±6.28, 18.6±8.68, and 22.5±4.47ng/ml following 10, 30, and 50mg doses, respectively, with the time of Cmax occurrence (tmax ) typically occurring at 2-12h post-dosing. Mean plasma buprenorphine terminal half-lives ranged between 78.3 and 91.2h. Increasing the dose threefold and fivefold from the 10mg dose increased the exposure by 2.8- and 3.6-fold, respectively, indicating that plasma buprenorphine exposure increased in a less than proportional manner at doses >30mg. Transient sedation, mydriasis, and euphoria were observed within 4h post-dosing. Mean rectal temperatures were increased 0.6-0.9°C greater than baseline (37.4-37.8°C) through 168h post-dosing. The absolute bioavailability was 16.0% (90% CI: [11.8%-21.7%]). Flip-flop pharmacokinetics were observed with a terminal elimination half-life of 0.82±0.13 and 64.9±15.0h for IV buprenorphine and 20mg of TBS, respectively. A single administration of TBS over a range of doses resulted in extended plasma buprenorphine concentrations and opioid physiological and behavioral effects.