Sublingual Buprenorphine/Naloxone Film in Unanesthetized Rats: Feasibility, Tolerability, and Plasma Exposure

ABSTRACT Background Buprenorphine/naloxone sublingual film is first-line treatment for opioid use disorder, yet preclinical rodent studies use routes that do not match clinical dosing. We tested sublingual film administration in unanesthetized rats. Methods Male Sprague-Dawley rats received film delivering 3.2 mg/kg buprenorphine, scaled from the 16 mg/day clinical dose by body surface area and corrected for species differences in sublingual bioavailability. Plasma buprenorphine was measured by LC-MS/MS after a single dose. Body weight, liver weight, serum AST, ALT and ALP, and liver histopathology were compared with controls after 21-days of once-daily dosing. Results Plasma buprenorphine peaked at 4.0 ng/mL at 2 h and was 0.9 ng/mL at 24 h, with an AUC(0-24h) of 39.0 h ng/mL, spanning concentrations reported as therapeutic in patients. Repeat dosing reduced absolute and relative liver weight and relative liver weight, with no change in serum enzymes or liver histology. Conclusions Sublingual film dosing is feasible and tolerated in unanesthetized rats and achieves clinically relevant buprenorphine exposure, enabling route-matched preclinical studies of buprenorphine pharmacology and opioid-related behavior.