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

• Published in: Clinical therapeutics 2008-11, Vol.30 (11), p.2051-2068
• Main Authors: Smith, Kevin, PhD, Hopp, Michael, MD, Mundin, Gill, BSc, Leyendecker, Petra, MSc, Bailey, Paul, BSc, Grothe, Birgit, Dipl.-Biol, Uhl, Reiner, BSc, Reimer, Karen, MD, PhD
• Format: Article
• Language: English
• Subjects: Administration, Oral; Adult; Anorexia - chemically induced; Area Under Curve; Arthritis; Biological and medical sciences; Biological Availability; Cancer therapies; Chronic pain; Clinical medicine; Clinical trials; Constipation; Cross-Over Studies; Delayed-Action Preparations - administration & dosage; Delayed-Action Preparations - adverse effects; Delayed-Action Preparations - pharmacokinetics; Diabetes; Diabetic neuropathy; Dose-Response Relationship, Drug; Drug Combinations; Drug dosages; Female; Half-Life; Headache - chemically induced; Humans; Internal Medicine; Male; Medical Education; Medical sciences; Middle Aged; Morphine; naloxone; Naloxone - administration & dosage; Naloxone - adverse effects; Naloxone - analogs & derivatives; Naloxone - metabolism; Naloxone - pharmacokinetics; Narcotic Antagonists; Narcotics; Nausea - chemically induced; Osteoarthritis; oxycodone; Oxycodone - administration & dosage; Oxycodone - adverse effects; Oxycodone - pharmacokinetics; Pain management; Patients; pharmacokinetics; Pharmacology. Drug treatments; prolonged release; Quality of life; Receptors, Opioid - agonists; Tablets; Therapeutic Equivalency
• ISSN: 0149-2918; 1879-114X
• DOI: 10.1016/j.clinthera.2008.11.008

Abstract 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 multipledose 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-ddose 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/mm2 ). The mean plasma oxycodone concentration-time curves for OXN and oxycodone PR + naloxone PR were similar. With oxycodone, the mean (SD) AUCt 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 Cmax 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) AUCt 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, respec