STEADY-STATE PHARMACOKINETICS OF HYDROMORPHONE AND HYDROMORPHONE-3-GLUCURONIDE IN CANCER-PATIENTS AFTER IMMEDIATE AND CONTROLLED-RELEASE HYDROMORPHONE

Although the pharmacokinetics of oral hydromorphone has been evaluated in healthy volunteers after small single oral doses, data are not ava ilable regarding the disposition of hydromorphone and its principal me tabolite, hydromorphone-3-glucuronide (H3G), at steady-state and after large oral doses. The authors studied the pharmacokinetics of hydromo rphone and H3G after oral administration of an immediate-release (IR) and controlled-release (CR) formulation of hydromorphone at a daily do se of 48+/-11 mg (range 6-216 mg) in a randomized, double-blind, stead y-state, two-way crossover evaluation in 18 patients with chronic canc er pain. Controlled-release hydromorphone demonstrated equivalent bioa vailability and acceptable CR characteristics, when compared with IR h ydromorphone (CR vs. IR: AUC(0-12) 123.10+/-20.38 vs. 118.98+/-20.92 n g.hr.mL(-1), P = NS, C-max 17.76+/-3.07 vs. 19.70+/-4.04 ng.mL(-1), P = N.S., C-min 6.04+/-1.01 vs. 5.28+/-1.00 ng.mL(-1), P = NS, and T-max 4.78+/-0.78 vs. 1.47+/-0.22 hr, P = 0.0008). A significant linear rel ationship 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 rati o of H3G to hydromorphone was 27:1. The authors conclude that CR hydro morphone provides a pharmacokinetic profile consistent with 12 hourly dosing and that at steady state, oral hydromorphone is extensively met abolized to H3G, although the pharmacologic activity of this metabolit e remains unknown.