Opioids: clinical pharmacology: Clinical pharmacology of hydromorphone hydrochloride extended-release capsules following multiple-dose oral administration

Abstract

A once-daily (q24h) hydromorphone hydrochloride extended-release (HHER) multiparticulate melt extrusion pellet formulation has been developed in capsule strengths of 12, 16, 24, and 32 mg. An extended-release formulation will avoid the need for frequent (q4-6h) administration of immediate-release hydromorphone (HHIR) to maintain analgesia in appropriate pain settings. On FDA approval, this product will be marketed as PalladoneTM Capsules. A randomized, multiple-dose, 2-way crossover study was conducted in healthy volunteers. Treatments consisted of a HHER 12-mg capsule q24h or a HHIR 3-mg tablet q6h each administered over a 5-day dosing period. For both treatments, predose (trough values) were assessed on days 1 through 5 while full PK profiles were obtained for 24 hours on day 5. The steady-state pharmacokinetics (PK) and safety profiles of hydromorphone (HMP) following HHER and HHIR dosing were determined. Plasma HMP concentrations were analyzed using a validated LC-MS/MS assay; appropriate PK and statistical methods were applied to the data obtained. Plasma HMP concentration profiles on day 5 were characterized by a much flatter profile for HHER q24h compared with HHIR q6h. Steady-state plasma HMP concentrations were achieved within 2 to 3 days following initiation of oral HHER dosing. Peak-to-trough fluctuation was approximately 2-fold or 200% lower for HHER than for HHIR. The total daily exposures of HHER and HHIR were bioequivalent. At steady state, HHER resulted in a lower Cmax, a later tmax, and a higher Cmin compared with the corresponding values obtained with HHIR. Following multiple dosing, HHER did not accumulate significantly with once-daily administration. Adverse events were those typically observed with opioid analgesics. Based on the multiple-dose PK and safety profiles, HHER is suitable for q24h administration.