Evaluation of the effect of naltrexone coadministration on the pharmacokinetics of oxycodone in a randomized phase 1 clinical trial

摘要

Objective: Oxycodone is a centrally acting mu-opioid agonist used as a strong analgesic. The opioid receptor antagonist naltrexone is often coadministered to healthy subjects in clinical trials evaluating the pharmacokinetics (PK) of oxycodone to minimize its pharmacodynamic opioid effects. One objective of this relative bioavailability trial in healthy subjects was to investigate the effect of naltrexone on the PK of oxycodone. Materials and methods: A randomized, single-dose, parallel-group, within-groups crossover, clinical trial was conducted in 24 healthy subjects. 12 subjects were to receive a new oxycodone prolonged-release (PR) tablet (test) with naltrexone (T+) and without naltrexone (T) in the fasted state. Additionally, 12 subjects were to receive an Oxygesic PR tablet (reference) with naltrexone (R+) and without naltrexone (R) in the fasted state. Naltrexone was given orally 1.5 hours prior to each oxycodone administration. Pharmacokinetics, safety, and tolerability were assessed. Results: The PK parameters of either oxycodone formulation were not changed with naltrexone administration under fasted conditions (point estimate T+/T (corresponding 90% confidence interval): C-max: 103% (88 - 119%), AUC(0-t): 97% (87 - 108%), AUC: 97% (88 - 108%); point estimate R+/R (corresponding 90% confidence interval): Cmax: 104% (97 - 112%), AUC(0-t): 95% (88 - 102%), AUC: 94% (87 - 100%)). The safety and tolerability of both formulations was not qualitatively affected by naltrexone coadministration; however, treatment with naltrexone coadministration showed lower frequencies of adverse events. Conclusion: Oral naltrexone does not affect the PK of oral oxycodone under fasted conditions. A naltrexone block can be applied in oxycodone PK trials to minimize adverse opioid effects.