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