Input Characteristics and Bioavailability after Administration of Immediate and a New Extended-release Formulation of Hydromorphone in Healthy Volunteers

Background To compare the pharmacokinetics of intravenous, oral immediate-release (IR), and oral extended-release (OROS®) formulations of hydromorphone. Methods In this randomized, six-session, crossover-design study, 12 subjects received hydromorphone 8-mg intravenous, 8-mg IR oral, and 8-, 16-, and 32-mg OROS® formulations or placebo orally followed by plasma sampling for hydromorphone determination. Pharmacokinetic analysis was performed using NONMEM. Using the disposition of hydromorphone from the intravenous administration, deconvolution was used to estimate the input rate function (release rate from the gut to the blood) for the IR and OROS® formulations. A linear spline was used to describe the drug input rate function. Results The deconvolution using linear splines described the in vivo release characteristics of both the IR and OROS® formulations. The mean absolute bioavailability for the 8-mg OROS® formulation was significantly larger (P = 0.025) than for the 8-mg IR formulation: 0.24 (SD 0.059) versus 0.19 (SD 0.054), respectively. The bioavailability was the same for the three doses of the OROS® formulation. Predicted degree of fluctuation of plasma concentrations would be expected to be 130% and 39% for the IR and OROS® 8-mg doses, respectively. Conclusions The OROS® formulation of hydromorphone produced continued release of medication over 24 h, which should allow for once-daily oral dosing. The extended release of hydromorphone will produce less fluctuation of plasma concentrations compared with IR formulations, which should provide for more constant pain control. The in vivo release of hydromorphone from both IR and OROS® formulations were adequately described using a linear spline deconvolution approach. The increased bioavailability from the OROS® formulation may be related to decreased metabolism by a first-pass effect or enterohepatic recycling of hydromorphone.