Pharmacokinetics and dose selection of a novel, long-acting transdermal fentanyl solution in healthy laboratory Beagles.
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 μL/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 ng·h/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 μL/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.
Nexcyon Pharmaceuticals, Inc., Madison, WI 53703, USA.
K J
KJ
Freise
M C
MC
Savides
K L
KL
Riggs
J G
JG
Owens
G C
GC
Newbound
T P
TP
Clark
D000279:Administration, Cutaneous; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D003692:Delayed-Action Preparations; D004285:Dogs / Q000097:blood*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006207:Half-Life; D008297:Male; D012996:Solutions
D000701:Analgesics, Opioid; D003692:Delayed-Action Preparations; D012996:Solutions; D005283:Fentanyl