Bioavailability of four different sublingual formulations of fentanyl in healthy male volunteers: Phase I, randomised, open-label, crossover study
Year: 2008
Session type: Poster / e-Poster / Silent Theatre session
1Orexo AB, 754 50 Uppsala, Sweden, 2ProStrakan Group plc, Galashiels, TD1 1QH, UK
Abstract
Background
A mucoadhesive sublingual fentanyl formulation (SLF), with rapid delivery of fentanyl into the systemic circulation, has been developed for cancer breakthrough pain. This open-label study characterised and compared the pharmacokinetics of three optimised SLF formulations (A, B and C) with a previously developed reference formulation (D).
Method
In a randomised, crossover design, opioid-naïve, healthy male subjects (n=16) received the four formulations as single doses (400 µg); each administration was separated by a ≥2-day washout. All subjects were pre-treated with naltrexone in order to block the opioid effects of fentanyl. The assessed pharmacokinetics included AUC, Cmax, and tmax. Adverse events (AEs) were monitored throughout. Bioequivalence was confirmed if the test/reference ratio was within the range 0.80–1.25 for AUC and Cmax.
Results
All subjects completed the study (mean age 25±4 years). Total systemic exposure (AUC(0–10h)) was highest with formulation A and lowest with formulation C (2.79; 2.47 ng.h/mL, respectively). A comparable Cmax was observed with formulations A, B and D (0.63; 0.61; 0.62 ng/mL, respectively), with the Cmax for formulation C being lower (0.55). tmax was attained rapidly in all cases, being shortest for formulation A (52.5 mins). The ratios for AUC(0–10h) and Cmax were within the
pre-specified range for formulations A (94.6–109.0; 89.2–114.7, respectively) and B (89.2–102.7; 86.1–110.8, respectively), suggesting bioequivalence to formulation D. The Cmax ratio for formulation C fell just outside the pre-specified range (AUC(0–10h): 83.4–96.1; Cmax:77.1–99.3). The AEs were typical of opioids (headache, nausea, dizziness); most (90.3%) were mild.
Conclusion
Formulations A and B were well tolerated and bioequivalent to reference formulation D. By optimising the formulation, the rate and extent of fentanyl absorption could be improved, as shown for formulation A.
Background
A mucoadhesive sublingual fentanyl formulation (SLF), with rapid delivery of fentanyl into the systemic circulation, has been developed for cancer breakthrough pain. This open-label study characterised and compared the pharmacokinetics of three optimised SLF formulations (A, B and C) with a previously developed reference formulation (D).
Method
In a randomised, crossover design, opioid-naïve, healthy male subjects (n=16) received the four formulations as single doses (400 µg); each administration was separated by a ≥2-day washout. All subjects were pre-treated with naltrexone in order to block the opioid effects of fentanyl. The assessed pharmacokinetics included AUC, Cmax, and tmax. Adverse events (AEs) were monitored throughout. Bioequivalence was confirmed if the test/reference ratio was within the range 0.80–1.25 for AUC and Cmax.
Results
All subjects completed the study (mean age 25±4 years). Total systemic exposure (AUC(0–10h)) was highest with formulation A and lowest with formulation C (2.79; 2.47 ng.h/mL, respectively). A comparable Cmax was observed with formulations A, B and D (0.63; 0.61; 0.62 ng/mL, respectively), with the Cmax for formulation C being lower (0.55). tmax was attained rapidly in all cases, being shortest for formulation A (52.5 mins). The ratios for AUC(0–10h) and Cmax were within the
pre-specified range for formulations A (94.6–109.0; 89.2–114.7, respectively) and B (89.2–102.7; 86.1–110.8, respectively), suggesting bioequivalence to formulation D. The Cmax ratio for formulation C fell just outside the pre-specified range (AUC(0–10h): 83.4–96.1; Cmax:77.1–99.3). The AEs were typical of opioids (headache, nausea, dizziness); most (90.3%) were mild.
Conclusion
Formulations A and B were well tolerated and bioequivalent to reference formulation D. By optimising the formulation, the rate and extent of fentanyl absorption could be improved, as shown for formulation A.
