Pharmacokinetics and dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles K. J. FREISE* M. C. SAVIDES   K. L. RIGGS à J. G. OWENS à G. C. NEWBOUND* & T. P. CLARK* *Nexcyon Pharmaceuticals, Inc., Madison, WI, USA;   Ricerca Biosciences, LLC, Toxicology and Pharmacology, Concord, OH, USA; à Elanco Animal Health, Greenfield, IN, USA Freise, K.J., Savides, M.C., Riggs, K.L., Owens, J.G., Newbound, G.C., Clark, T.P. Pharmacokinetics and dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles. J. vet. Pharmacol. Therap. 35 (Suppl. 2), 21–26. A novel, transdermal fentanyl solution (TFS) was developed that delivers sustained concentrations of fentanyl for days following a single application. The pharmacokinetics following a single topical dose was examined. Eighteen adult Beagle dogs were divided into three groups of six dogs (3M, 3F). Each group was administered a single dose of 1.3 (25), 2.6 (50), or 5.2 mg ⁄ kg (100 lL ⁄ kg) of TFS. The dose was applied to the clipped, ventral abdominal skin using a 1-mL tuberculin syringe. Immediately following dosing, collars were placed on each dog through 72 h to prevent direct licking of the application site. Serial jugular venous blood samples were collected at 0 (predosing), 1, 2, 4, 6, 8, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 144, 168, 240, 336, 408, and 504 h after dosing and assayed for plasma fentanyl concentration. Fentanyl was rapidly detected following application with a mean absorption lag time (t lag ) of 0.333 h in the 1.3 mg ⁄ kg group and 0 in the other two groups. The mean C max increased with dose and were 2.28, 2.67, and 4.71 ng ⁄ mL in the 1.3, 2.6 and 5.2 mg ⁄ kg dose groups, respectively. Mean terminal half-lives were 53.7, 69.6, and 103 h in the 1.3, 2.6, and 5.2 mg ⁄ kg dose groups, respectively. The mean AUC 0-LLOQ from lowest to highest dose groups were 157, 268, and 645 ngÆh ⁄ mL and were dose proportional with a R 2 value of 0.9818. Adverse reactions were limited to the highest dose group and included sedation (four of six dogs) and decreased food and water intake (one dog). A dose of 2.6 mg ⁄ kg (50 lL ⁄ kg) is proposed for further development studies based on the lack of adverse events that were observed compared to the 5.2 mg ⁄ kg group and a more rapid onset of action and longer duration of action compared to the 1.3 mg ⁄ kg group. (Paper received 30 January 2012; accepted for publication 20 March 2012) Dr Terrence Clark, Nexcyon Pharmaceuticals, Inc., 644 W. Washington Ave., Madison, WI 53703, USA. E-mail: clarktp@nexcyon.com INTRODUCTION Opioids are generally regarded as an important part of multi- modal perioperative analgesia, especially for moderate to severe pain. In human health, the use of opioids during and after surgery for most soft tissue and orthopedic surgeries is consid- ered the standard of care and are included in procedure-specific treatment algorithms. (Neugebauer et al., 2007) In veterinary medicine, the use of opioids in dogs beyond the immediate postoperative period is prevented by inherent limitations of most opioids including poor oral bioavailability and rapid clearance. (Pascoe, 2000) As a result, opioid use is primarily limited to single or repeat perioperative parenteral injections or constant rate intravenous infusions (CRI) delivered during anesthesia. Fentanyl is a potent, full l-opioid receptor agonist having approximately 100-fold the analgesic potency of morphine (Adams, 2001). Poor oral bioavailability and rapid clearance have limited fentanyl’s use primarily to perioperative parenteral doses. Following intravenous (IV) administration of fentanyl citrate to dogs, the elimination half-life has been reported to range from 0.76 to 6.0 h (Murphy et al., 1983; Kyles et al., 1996; Hughes & Nolan, 1999; Sano et al., 2006). To overcome these limitations and prolong the therapeutic duration of action, variations in pharmaceutical delivery have been advanced for use in human health. For prolonged use to treat moderate to severe chronic pain in humans, patches intended as devices to deliver fentanyl transdermally have been developed (Janssen Pharmaceutica Products, 2005). Although specifically contra- J. vet. Pharmacol. Therap. 35 (Suppl. 2), 21–26. doi: 10.1111/j.1365-2885.2012.01399.x Ó 2012 Blackwell Publishing Ltd 21