Steady‐State Pharmacokinetics of Hydromorphone and Hydromorphone‐3‐Glucuronide in Cancer Patients After Immediate and Controlled‐Release Hydromorphone

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Abstract
Although the pharmacokinetics of oral hydromorphone has been evaluated in healthy volunteers after small single oral doses, data are not available regarding the disposition of hydromorphone and its principal metabolite, hydromorphone-3-glucuronide (H3G), at steady-state and after large oral doses. The authors studied the pharmacokinetics of hydromorphone and H3G after oral administration of an immediate-release (IR) and controlled-release (CR) formulation of hydromorphone at a daily dose of 48 ± 11 mg (range 6–216 mg) in a randomized, double-blind, steady-state, two-way crossover evaluation in 18 patients with chronic cancer pain. Controlled-release hydromorphone demonstrated equivalent bioavailability and acceptable CR characteristics, when compared with IR hydromorphone (CR vs. IR: AUC0–12 123.10 ± 20.38 vs. 118.98 ± 20.92 ng · hr · mL−1, P = NS, Cmax 17.76 ± 3.07 vs. 19.70 ± 4.04 ng · mL−1, P = N.S., Cmin 6.04 ± 1.01 vs. 5.28 ± 1.00 ng · mL−1, P = NS, and Tmax 4.78 ± 0.78 vs. 1.47 ± 0.22 hr, P = 0.0008). A significant linear relationship existed between hydromorphone dose and hydromorphone AUC (r = 0.8315, P = 0.0001) and between hydromorphone AUC and H3G AUC (r = 0.8048, P = 0.0001) over a wide dose range. The steady-state molar ratio of H3G to hydromorphone was 27:1. The authors conclude that CR hydromorphone provides a pharmacokinetic profile consistent with 12 hourly dosing and that at steady state, oral hydromorphone is extensively metabolized to H3G, although the pharmacologic activity of this metabolite remains unknown.