Single- and multiple-dose pharmacokinetic evaluation of oxycodone and naloxone in an opioid agonist/antagonist prolonged-release combination in healthy adult volunteers

Kevin Smith, Michael Hopp, Gill Mundin, Petra Leyendecker, Paul Bailey, Birgit Grothe, Reiner Uhl, Karen Reimer
Clinical Therapeutics 2008, 30 (11): 2051-68

BACKGROUND: There is an increasing body of evidence supporting the need for prophylactic management of the adverse events (AEs) associated with long-term opioid use in patients with chronic pain. Symptoms of bowel dysfunction, such as constipation, may have a significant impact on a patient's quality of life and willingness to continue opioid therapy, and therefore should be managed proactively to ensure that the patient can continue effective pain management. The fixed-dose combination (FDC) prolonged-release (PR) oxycodone/naloxone (OXN) may be an effective therapeutic approach to delivering analgesia, with a reduced risk for opioid-induced constipation.

OBJECTIVE: The aim of this paper was to report the pharmacokinetic results from a single-dose study and a multiple-dose bioequivalence study of OXN versus separate formulations of oxycodone PR and naloxone PR administered concurrently in healthy subjects.

METHODS: Both studies were open-label, randomized crossover studies in healthy adult male and female subjects. In the single-dose study, subjects were randomly assigned to 1 of 4 treatment groups: OXN FDC (44 x 10/55-mg, 2 x 20/110-mg, or 1 x 40/20-mg dose strength [each given at a total combined dose of 40/220 mg]) or oxycodone PR 40 mg + naloxone PR 20 mg given in separate formulations. In the multiple-dose study, 34 subjects were randomly assigned to 1 of 3 treatment groups: OXN FDC 40/20 mg, oxycodone PR 40 mg, or naloxone PR 20 mg. Treatments were considered bioequivalent if the 90% CIs for relative bioavailability calculations fell within a predetermined range of 80% to 125%. AEs were assessed by the investigator at each study visit.

RESULTS: The single-dose study included 28 subjects (22 men, 6 women; mean [SD] age, 32.3 [5.44] years; weight, 75.5 [9.3] kg; and body mass index [BMI], 24.2 [2.5] kg/mm(2)). The mean plasma oxycodone concentration-time curves for OXN and oxycodone PR + naloxone PR were similar. With oxycodone, the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 473.49 (72.16), 491.22 (82.18), 488.89 (91.04), and 502.28 (84.13) ng . h/mL, respectively; mean C(max) values were 34.91 (4.36), 35.73 (4.93), 34.46 (5.03), and 40.45 (4.71) ng/mL. For naloxone-3-glucuronide (the primary analyte of naloxone), the mean (SD) AUC(t) values with OXN 10/5, 20/10, and 40/20 mg and oxycodone PR + naloxone PR were 539.93 (142.24), 522.45 (128.57), 520.10 (133.18), and 523.37 (119.75) ng . h/mL, respectively; mean C(max) values were 62.01 (15.96), 63.62 (19.51), 61.95 (18.37), and 63.55 (16.75) ng/mL. There were no statistically significant differences between the treatments, and each of the treatment comparisons resulted in 90% CIs within the range for bioequivalence. The multiple-dose steady-state bioequivalence study included 34 subjects (28 men, 6 women; mean [SD] age, 36 [9.4] years; weight,78.9 [11.7] kg; and BMI, 24.6 [1.9] kg/m(2)). No significant differences were observed between the treatments, with the exception of naloxone-3-glucuronide C(min,ss) values. Mean C(min,ss) values of 22.6 and 24.0 ng/mL were obtained for the OXN combination and naloxone PR tablet, respectively. In the multiple-dose study, the most frequently reported AEs with OXN,oxycodone PR, and naloxone PR were headache (7%, 26%, and 17%, respectively), anorexia (10%, 16%, and 13%), and nausea (10%, 13%, and 7%).

CONCLUSIONS: The results from the single-dose study were consistent with the regulatory definition of bioequivalence of the FDCs and single components across the range of doses administered. The pharmacokinetic properties of the OXN FDC were similar to those of oxycodone PR + naloxone PR given as separate formulations, based on the regulatory definition. These findings were consistent with the results of the multiple-dose steady-state bioequivalence study. In this population of healthy volunteers, the pharmacokinetic properties of oxycodone apparently were not significantly influenced by administering oxycodone in a combination product, and the availability of naloxone-3-glucuronide from OXN was similar to that from the naloxone PR tablet. These findings suggest that the coadministration of oxycodone PR and naloxone PR in an FDC would not significantly affect the bioavailability of either of its constituents in these subjects.

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