Dose proportionality of fentanyl buccal tablet 600 to 1300 μg in healthy volunteers

Abstract

Fentanyl buccal tablet (FBT), which provides rapid-onset analgesia, enhances fentanyl absorption across the buccal mucosa. In a pilot study, dose proportionality for FBT was established only up to 1000 μg. The current study was conducted to evaluate dose proportionality over an extended dose range (up to 1300 μg). Healthy volunteers received FBT as one 600 μg tablet, one 1000 μg tablet, one 1200 μg tablet, and one 800 μg plus 400 μg plus 100 μg tablet (1300 μg) in a randomized, crossover fashion with a ≥7-day washout between doses. As volunteers were not opioid-tolerant, naltrexone was administered to minimize opioid effects. Plasma fentanyl (from venous blood) was measured through 72 hours post dose. Peak plasma fentanyl concentration (Cmax) and area under the plasma concentration-vs-time curve (AUC0-∞) were evaluated, and dose proportionality was to be concluded if the 2-sided 90% confidence intervals (CIs) for the slopes of the Cmax vs dose and AUC0-∞ vs dose curves were completely within the limits of 0.711 to 1.289. Safety and tolerability were monitored throughout the study. 109 volunteers were enrolled (mean age 28 years, 51% male); 88 completed the study. The slopes (90% CI) for Cmax vs dose and AUC0-∞ vs dose were 0.8627 (0.7730, 0.9525) and 0.9330 (0.8738, 0.9922), respectively. CIs were contained completely within the prespecified limits, indicating that FBT was dose proportional from 600 to 1300 μg. 74 subjects (68%) experienced ≥1 adverse event (AE), either mild (n = 56 subjects) or moderate (n = 18 subjects) in severity. The most common AEs were nausea, dizziness and headache. Treatment-emergent AEs led to study withdrawal of 2 volunteers. In conclusion, FBT was dose proportional over the range 600 to 1300 μg, indicating that a predictable, linear increase in systemic exposure may be expected across this range when FBT is titrated to an effective dose. Fentanyl buccal tablet (FBT), which provides rapid-onset analgesia, enhances fentanyl absorption across the buccal mucosa. In a pilot study, dose proportionality for FBT was established only up to 1000 μg. The current study was conducted to evaluate dose proportionality over an extended dose range (up to 1300 μg). Healthy volunteers received FBT as one 600 μg tablet, one 1000 μg tablet, one 1200 μg tablet, and one 800 μg plus 400 μg plus 100 μg tablet (1300 μg) in a randomized, crossover fashion with a ≥7-day washout between doses. As volunteers were not opioid-tolerant, naltrexone was administered to minimize opioid effects. Plasma fentanyl (from venous blood) was measured through 72 hours post dose. Peak plasma fentanyl concentration (Cmax) and area under the plasma concentration-vs-time curve (AUC0-∞) were evaluated, and dose proportionality was to be concluded if the 2-sided 90% confidence intervals (CIs) for the slopes of the Cmax vs dose and AUC0-∞ vs dose curves were completely within the limits of 0.711 to 1.289. Safety and tolerability were monitored throughout the study. 109 volunteers were enrolled (mean age 28 years, 51% male); 88 completed the study. The slopes (90% CI) for Cmax vs dose and AUC0-∞ vs dose were 0.8627 (0.7730, 0.9525) and 0.9330 (0.8738, 0.9922), respectively. CIs were contained completely within the prespecified limits, indicating that FBT was dose proportional from 600 to 1300 μg. 74 subjects (68%) experienced ≥1 adverse event (AE), either mild (n = 56 subjects) or moderate (n = 18 subjects) in severity. The most common AEs were nausea, dizziness and headache. Treatment-emergent AEs led to study withdrawal of 2 volunteers. In conclusion, FBT was dose proportional over the range 600 to 1300 μg, indicating that a predictable, linear increase in systemic exposure may be expected across this range when FBT is titrated to an effective dose.