Pharmacokinetics and Dose-Proportionality of Oxymorphone Extended Release and Its Metabolites: Results of a Randomized Crossover Study

Michael P. Adams, Pharm.D.; Harry Ahdieh, Ph.D.


Pharmacotherapy. 2004;24(4) 

In This Article

Abstract and Introduction

Study Objective: To evaluate the pharmacokinetics and dose-proportionality of four dose strengths (5, 10, 20, and 40 mg) of oxymorphone extended release (ER) under both single-dose and steady-state conditions.
Design: Randomized, three-period, four-sequence, crossover study.
Setting: Bioavailability clinic.
Subjects: Twenty-four healthy adult volunteers.
Intervention: Each subject received three of the four possible doses. The three 8-day administration periods were separated by a 7-day washout. Plasma was collected for up to 48 hours after a single dose on day 1 and during a 12-hour dosage interval at steady state. Naltrexone was administered to reduce opioid-related adverse effects.
Measurements and Main Results: Twenty-three subjects completed at least one study period. Dose-proportionality and linearity were confirmed after single doses (mean oxymorphone ER area under the concentration versus time curve [AUC] 4.54, 8.94, 17.80, and 37.90 ng•hr/ml for 5-, 10-, 20-, and 40-mg doses, respectively) and at steady state (mean oxymorphone ER AUC 5.60, 9.77, 19.3, and 37.0 ng•hr/ml for 5-, 10-, 20-, and 40-mg doses every 12 hrs, respectively). Similar results were found for maximum plasma concentration. Metabolite (6-hydroxyoxymorphone and oxymorphone-3-glucuronide) plasma levels also increased in a linear fashion after single-dose administration and at steady state.
Conclusion: The pharmacokinetic profile of oxymorphone ER demonstrates linearity and dose-proportionality under single-dose and steady-state conditions for the parent compound and its metabolites for doses of 5-40 mg.

The undertreatment of patients with chronic malignant and nonmalignant pain remains an important clinical issue.[1] Opioid therapy (alone or in combination with other analgesic approaches) is widely used in patients with moderate or severe cancer pain[2,3] and in patients with chronic nonmalignant pain when analgesia provided by other therapies (e.g., nonsteroidal antiinflammatory drugs, transcutaneous electrical nerve stimulation) is no longer adequate.[4] Optimal management of chronic pain requires around-the-clock coverage with analgesic agents. Agents that provide a sustained release of drug allow the patient to obtain this baseline analgesia with minimal doses/day, thereby improving patient compliance and minimizing interference with activities of daily living.[5] The Agency for Healthcare Research and Quality determined that parenteral (intramuscular or intravenous) administration offers little pain relief advantage over enteral administration and that sustained-release oral formulations provide an implicit advantage by reducing the administration frequency.[6] A meta-analysis of eight trials that compared oral sustained-release morphine with oral immediate-release morphine solution found comparable, but prolonged, pain relief with sustained-release delivery.[6]

Oxymorphone hydrochloride (14-hydroxy-dihydromorphinone) is a semisynthetic μ-opioid agonist[7] that has a more rapid onset of action and several times the analgesic potency of its parent compound morphine.[7,8] Oxymorphone is metabolized primarily to 6-hydroxyoxymorphone (6-OH-OXM) and oxymorphone-3-glucuronide (OXM-3-G) in the liver; less than 2% of parent drug is recovered unchanged in urine.[9] The pharmacologic activity of the glucuronide metabolite has not been evaluated; 6-OH-OXM has been shown in animal studies to have analgesic bioactivity.[10]

Oxymorphone extended release (ER) is a new sustained-release tablet formulation of oxymorphone hydrochloride developed to provide 12 hours of sustained analgesia.[10] The ER matrix, TIMERx (Penwest Pharmaceuticals Co., Danbury, CT), alters and delays drug dissolution and absorption from the gastrointestinal tract, thereby changing the pharmacokinetic profile relative to immediate-release drug formulations. Drug release from the ER matrix is controlled by the rate of penetration of water into the hydrophilic matrix and the subsequent expansion of the gel coating. Linearity of pharmacokinetic parameters contributes to a predictable dose response and aids in the design of clinical trials to examine the efficacy and safety of oxymorphone ER in the management of moderate-to-severe malignant and nonmalignant pain.

This study was undertaken to determine single and steady-state dose pharmacokinetics and dose-proportionality of oxymorphone and its metabolites (6-OH-OXM and OXM-3-G) across a dose range of 5-40 mg.


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