Pharmacokinetic investigation of dose proportionality with a 24-hour controlled-release formulation of hydromorphone

BACKGROUND: The purpose of this study was investigate the dose proportionality of a novel, once-daily, controlled-release formulation of hydromorphone that utilizes the OROS(® )Push-Pull™ osmotic pump technology. METHODS: In an open-label, four-way, crossover study, 32 healthy volunteers were randomized to receive a single dose of OROS(® )hydromorphone 8, 16, 32, and 64 mg, with a 7-day washout period between treatments. Opioid antagonism was provided by three or four doses of naltrexone 50 mg, given at 12-hour intervals pre- and post-OROS(® )hydromorphone dosing. Plasma samples for pharmacokinetic analysis were collected pre-dose and at regular intervals up to 48 hours post-dose (72 hours for the 64-mg dose), and were assayed for hydromorphone concentration to determine peak plasma concentration (C(max)), time at which peak plasma concentration was observed (T(max)), terminal half-life (t(1/2)), and area under the concentration-time curve for zero to time t (AUC(0-t)) and zero to infinity (AUC(0–∞)). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC(0-t), AUC(0–∞), and C(max )was used to establish dose linearity and proportionality. RESULTS: The study was completed by 31 of 32 subjects. Median T(max )(12.0–16.0 hours) and mean t(1/2 )(10.6–11.0 hours) were found to be independent of dose. Regression analyses of C(max), AUC(0–48), and AUC(0–∞ )by dose indicated that the relationship was linear (slope, P ≤ 0.05) and that the intercept did not differ significantly from zero (P > 0.05). Similar analyses with dose-normalized parameters also indicated that the slope did not differ significantly from zero (P > 0.05). CONCLUSION: The pharmacokinetics of OROS(® )hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses. TRIAL REGISTRATION: Clinical Trials.gov NCT00398957