IntroductionOxymorphone hydrochloride (referred to as oxymorphone), a semisynthetic μ-opioid agonist, is known to produce a more rapid onset of action and greater analgesic potency compared with its parent compound, morphine. Until recently, oxymorphone has been available only in suppository and intravenous formulations. This study examined the pharmacokinetics and dose proportionality of a new immediate-release (IR) tablet formulation of oxymorphone and its metabolites (6-OH-oxymorphone and oxymorphone-3-glucuronide) following single- and multiple-dose administration in healthy volunteers.Study designA randomised, three-way crossover design was employed, with a target sample size of 24 healthy men and women.MethodsA single dose of oxymorphone IR (5, 10 and 20mg) was administered on day 1. After drug washout on day 2, study participants then received the same dose every 6 hours (22 total doses) on days 3 to 8. Treatment periods were separated by a 7-day washout. Naltrexone hydrochloride was coadministered to prevent opioid-related adverse events. Blood was collected up to 48 hours after day 1 to determine single-dose pharmacokinetics and up to 6 hours after the last dose for determination of pharmacokinetics at steady state.ResultsTwenty-three of 24 enrolled subjects (12 men, 11 women) completed the study. Following a single dose of 5, 10 or 20mg, the oxymorphone IR mean area under the plasma concentration versus time curve from time zero to infinity ([AUC∞] 4.5, 9.1 and 20.1 μg · h/L, respectively) and maximum plasma concentration ([Cmax] 1.1, 1.9 and 4.4 μg/L, respectively) confirmed dose proportionality. 6-OH-oxymorphone and oxymorphone-3-glucuronide also increased in an approximate 2-fold fashion. Similar results were observed for AUC and Cmaxof oxymorphone and its metabolites at steady state. Steady state was achieved within 3 days of 6-hourly administration. The median tmax(time to reach Cmax) was 0.5 hours for all single doses of oxymorphone and at steady state, and the terminal elimination half-life (t½) was approximately 7.3–9.4 hours. Adverse events were generally mild, and no clinically significant changes in laboratory or other safety variables were noted.DiscussionBecause successful pain management often requires careful drug titration across a wide therapeutic dose range, it is important that opioid formulations provide predictable increases in drug concentration with increasing dose. The single-dose and steady-state pharmacokinetic profiles of oxymorphone IR tablets were linear and dose proportional across the dose range from 5 to 20mg.