Pharmacokinetics and Dose‐Proportionality of Oxymorphone Extended Release and Its Metabolites: Results of a Randomized Crossover Study

Abstract

Study Objective. To evaluate the pharmacokinetics and dose‐proportionality of four dose strengths (5, 10, 20, and 40 mg) of oxymorphone extended release (ER) under both single‐dose and steady‐state conditions. Design. Randomized, three‐period, four‐sequence, crossover study. Setting. Bioavailability clinic. Subjects. Twenty‐four healthy adult volunteers. Intervention. Each subject received three of the four possible doses. The three 8‐day administration periods were separated by a 7‐day washout. Plasma was collected for up to 48 hours after a single dose on day 1 and during a 12‐hour dosage interval at steady state. Naltrexone was administered to reduce opioid‐related adverse effects. Measurements and Main Results. Twenty‐three subjects completed at least one study period. Dose‐proportionality and linearity were confirmed after single doses (mean oxymorphone ER area under the concentration versus time curve [AUC] 4.54, 8.94, 17.80, and 37.90 ng·hr/ml for 5‐, 10‐, 20‐, and 40‐mg doses, respectively) and at steady state (mean oxymorphone ER AUC 5.60, 9.77, 19.3, and 37.0 ng·hr/ml for 5‐, 10‐, 20‐, and 40‐mg doses every 12 hrs, respectively). Similar results were found for maximum plasma concentration. Metabolite (6‐hydroxyoxymorphone and oxymorphone‐3‐glucuronide) plasma levels also increased in a linear fashion after single‐dose administration and at steady state. Conclusion. The pharmacokinetic profile of oxymorphone ER demonstrates linearity and dose‐proportionality under single‐dose and steady‐state conditions for the parent compound and its metabolites for doses of 5–40 mg.