49 - The Pharmacodynamics and Pharmacokinetics of Buprenorphine Buccal Film Versus Oral Oxycodone Hydrochloride: Results of a Phase 1 Placebo-Controlled Trial
Lynn Webster1, Jacqueline Cater1, Thomas Smith2
1PRA Health Sciences, Salt Lake City, UT, USA. 2BioDelivery Sciences International, Inc., Raleigh, NC, USA
Purpose Buprenorphine is a Schedule III atypical opioid that functions by binding to various opioid receptors located throughout the central nervous system to elicit analgesia. Buprenorphine acts as a partial agonist with high binding affinity at the mu-opioid receptor, an antagonist with high binding affinity at the delta- and kappa-opioid receptors, and an agonist with low binding affinity at opioid receptor-like 1. Unlike full mu-opioid receptor agonists (eg, fentanyl, morphine, oxycodone), buprenorphine has been shown to have a ceiling effect on respiratory depression, which is attributed to its unique pharmacodynamic and pharmacokinetic properties. Recently, a phase 1 placebo-controlled study compared the pharmacologic properties of buprenorphine buccal film (BELBUCA®, BioDelivery Sciences International, Inc.), a US Food and Drug Administration–approved treatment for chronic pain, with those of the full mu-opioid receptor agonist oxycodone hydrochloride (clinicaltrials.gov, NCT03996694). This study found that buprenorphine buccal film did not significantly impact various pharmacodynamic measures of respiratory drive, including the maximum decrease in minute ventilation as well as changes in minute ventilation and peak expiratory flow rates over time; whereas oxycodone decreased each of these parameters relative to placebo. Pharmacokinetic properties, including maximum observed plasma concentration (Cmax), time to attain maximum observed plasma concentration (Tmax), area under the plasma concentration versus time curve from 0 to the last measurable concentration (AUC0-last), and the abuse quotient (AQ; the ratio of Cmax to Tmax), were also assessed for buprenorphine buccal film and oxycodone. Methods This was a randomized, double-blind, double-dummy, 6-period, 6-treatment, placebo-controlled, crossover study, which compared the effects of buprenorphine buccal film (300, 600, or 900 μg) with those of oral immediate-release oxycodone hydrochloride (30 or 60 mg) and matching placebo on respiratory drive in recreational opioid users. Each treatment was separated by a 7-day washout period to avoid any unintentional carryover effects. Before randomization, subjects were determined not to be dependent on opioids via a Naloxone Challenge Test. Pharmacokinetic assessments were evaluated using blood samples collected pre-dose and at 0.5, 1, 2, 3, 4, and 6 hours post-dose to obtain Cmax, Tmax, AUC0-last, and AQ. These parameters were calculated using non-compartmental methods. Results A total of 19 subjects (18 [94.7%] men, 1 [5.3%] woman) were enrolled, and 15 (78.9%) completed the study. After the administration of 300, 600, or 900 μg of buprenorphine buccal film, Cmax increased proportionally with dose, with mean (SD) values of 0.4 (0.2), 0.8 (0.9), and 1.1 (0.4) ng/mL, respectively. The Cmax of immediate-release oxycodone also increased proportionally with dose, with mean (SD) values of 65.8 (19.1) ng/mL for 30 mg and 132 (46.2) ng/mL for 60 mg. The buccal film formulation of buprenorphine exhibited rapid absorption across all dosage strengths. For 300, 600, and 900 μg of buprenorphine buccal film, the median (minimum, maximum) Tmax values were similar at 2.2 (2.1, 3.2), 3.1 (1.1, 6.0), and 2.2 (2.1, 6.0) hours, respectively. The Tmax for immediate-release oxycodone was also similar between doses; the median (minimum, maximum) was 1.2 (0.6, 3.2) hours for the 30-mg dose and 1.2 (0.7, 6.0) hours for the 60-mg dose, suggesting faster absorption than buprenorphine buccal film. For both study drugs, AUC0-last increased proportionally with dose; the mean (SD) was 1.8 (1.2), 2.9 (2.5), and 4.0 (1.0) h*ng/mL for buprenorphine buccal film 300, 600, and 900 μg, respectively, and 216 (49.4) and 435 (141) h*ng/mL for immediate-release oxycodone 30 and 60 mg, respectively. AQ was low and similar among all doses of buprenorphine buccal film, with mean (SD) values of 0.2 (0.1) for 300 μg, 0.3 (0.2) for 600 μg, and 0.4 (0.1) for 900 μg. For immediate-release oxycodone, the AQ was higher than for buprenorphine buccal film, with mean (SD) values of 67.4 (39.2) for oxycodone 30 mg and 110 (75.3) for oxycodone 60 mg. Conclusions The unique pharmacokinetic properties of buprenorphine buccal film resulted in a slower absorption and lower AQ than immediate-release oral oxycodone. As higher AQ is associated with greater drug liking and abuse potential, these data could aid clinicians in proper medication and dose selection for patients who have been determined by risk-benefit analysis to be candidates for use of opioids in the management of chronic pain. Opioids are commonly used recreationally and carry a high risk of diversion; therefore, choosing a medication with less drug liking and abuse potential is imperative during the current opioid crisis. Taken together, these data further support the safety of buprenorphine buccal film over full mu-opioid receptor agonists for the treatment of chronic pain.