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(R)) 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(R) 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(R) 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(R) formulations. The mean absolute bioavailability for the 8-mg OROS(R) 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(R) formulation. Predicted degree of fluctuation of plasma concentrations would be expected to be 130% and 39% for the IR and OROS(R) 8-mg doses, respectively.