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

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 (Cmax), time at which peak plasma concentration was observed (Tmax), terminal half-life (t1/2), and area under the concentration-time curve for zero to time t (AUC0-t) and zero to infinity (AUC0–∞). An analysis of variance (ANOVA) model on untransformed and dose-normalized data for AUC0-t, AUC0–∞, and Cmax was used to establish dose linearity and proportionality.The study was completed by 31 of 32 subjects. Median Tmax (12.0–16.0 hours) and mean t1/2 (10.6–11.0 hours) were found to be independent of dose. Regression analyses of Cmax, AUC0–48, and AUC0–∞ 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).The pharmacokinetics of OROS？ hydromorphone are linear and dose proportional for the 8, 16, 32, and 64 mg doses.Clinical Trials.gov NCT00398957Hydromorphone hydrochloride (HCl), which is available in immediate- and extended-release formulations, is a semi-synthetic opioid agonist that has been used widely for many years in the treatment of acute and chronic pain. A number of studies have demonstrated the efficacy and tolerability of hydromorphone in comparison with morphine and other opioid analgesic agents [1]. When formulated as an immediate-release preparation, hydromorphone h