The pharmacokinetics of oxycodone and its metabolites following single oral doses of Remoxy®, an abuse-deterrent formulation of extended-release oxycodone, in patients with hepatic or renal impairment

Bimal K. Malhotra, PhD; Grant L. Schoenhard, PhD; Annelies W. de Kater, PhD; Nadav Friedmann, PhD, MD

doi:10.5055/jom.2015.0265

Authors

Bimal K. Malhotra, PhD
Grant L. Schoenhard, PhD
Annelies W. de Kater, PhD
Nadav Friedmann, PhD, MD

DOI:

https://doi.org/10.5055/jom.2015.0265

Keywords:

Remoxy, renal impairment, hepatic impairment, oxycodone, pharmacokinetics

Abstract

Objective: Remoxy® (Pain Therapeutics, Inc., Austin, TX) is an abuse-deterrent formulation of extended-release oxycodone. The effects of renal or hepatic impairment on the pharmacokinetics (PK) of single, oral doses of Remoxy 20 or 10 mg, respectively, were assessed in two phase 1 studies in subjects aged 18-80 years.

Methods: PK parameters included maximum plasma concentration (Cmax) and area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC0-t), and extrapolated to infinity (AUCinf). Adverse events (AEs) were monitored.

Results: Mean (SD) oxycodone Cmax values following Remoxy 20-mg administration were 17.6 (9.1), 21.9 (11.2), 25.9 (18.2), and 31.6 (14.5) ng/mL and AUC0-t values were 210.7 (82.1), 271.6 (83.3), 299.5 (76.3), and 493.5 (175.9) ng·h/mL in subjects with normal or mild (n = 6 each), moderate (n = 5), and severely impaired renal function (n = 6), respectively. Mean (SD) oxycodone Cmax following Remoxy 10-mg administration was 7.6 (3.3), 7.8 (2.3), and 13.1 (5.3) ng/mL and AUC0-t was 105.7 (49.5), 134.7 (38.3), and 218.0 (74.1) ng·h/mL in subjects with normal, mild, and moderately impaired hepatic function (n = 6 each), respectively. Differences in exposure values between the different renal and hepatic groups were significant. Treatment-emergent AEs were reported by 14.3, 66.7, 66.7, and 50.0 percent of subjects with normal, mild, moderate, and severely impaired renal function, respectively, and by 50.0, 33.3, and 66.7 percent of subjects with normal, mild, and moderately impaired hepatic function, respectively.

Conclusions: As renal or hepatic function decreased, oxycodone Cmax and AUC0-t were up to approximately twofold higher following single, oral doses of extended-release Remoxy. AEs were those typically reported for opioids. Lower doses of Remoxy may thus be safely prescribed to subjects with renal or hepatic impairment.

Author Biographies

Bimal K. Malhotra, PhD

Senior Director, Pfizer Inc, New York, New York

Grant L. Schoenhard, PhD

Chief Scientific Officer, Pain Therapeutics, Inc., Austin, Texas

Annelies W. de Kater, PhD

Pain Therapeutics, Inc., Austin, Texas

Nadav Friedmann, PhD, MD

Chief Operating and Medical Officer, Pain Therapeutics, Inc., Austin, Texas

References

US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality: Results from the 2012 National Survey on Drug Use and Health: Summary of National Findings. NSDUH Series H-46. HHS Publication No. (SMA) 13-4795. Available at http://www.samhsa.gov/data/NSDUH/2012SummNatFindDetTables/DetTabs/NSDUHDetTabsSect1peTabs1to46-2012.htm#Tab1.18A. Accessed August 14, 2014.

US Department of Health and Human Services, Substance Abuse and Mental Health Services Administration, Center for Behavioral Health Statistics and Quality: Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. HHS Publication No. (SMA) 13-4760. DAWN Series D-39. Available at http://www.samhsa.gov/data/2k13/DAWN2k11ED/DAWN2k11ED.htm. Accessed August 14, 2014.

US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics: Health, United States, 2012: With Special Feature on Emergency Care. Available at http://www.cdc.gov/nchs/data/hus/hus12.pdf. Accessed August 14, 2014.

US Department of Health and Human Services Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Guidance for Industry: Abuse-Deterrent Opioids—Evaluation and Labeling. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM334743.pdf. Accessed August 14, 2014.

Hamburg MA, US Food and Drugs Administration: 2013 National Rx Drug Abuse Summit. Available at http://www.fda.gov/NewsEvents/Speeches/ucm346315.htm. Accessed August 14, 2014.

Friedmann N, Klutzaritz V, Webster L: Efficacy and safety of an extended-release oxycodone (Remoxy) formulation in patients with moderate to severe osteoarthritic pain. J Opioid Manag. 2011; 7(3): 193-202.

Friedmann N, Klutzaritz V, Webster L: Long-term safety of Remoxy® (extended-release oxycodone) in patients with moderate to severe chronic osteoarthritis or low back pain. Pain Med. 2011; 12(5): 755-760.

Setnik B, Roland CL, Cleveland JM, et al.: The abuse potential of Remoxy(®), an extended-release formulation of oxycodone, compared with immediate- and extended-release oxycodone. Pain Med. 2011; 12(4): 618-631.

Zamloot M, Chao W, Kang L, et al.: Remoxy®: A novel formulation of extended-release oxycodone developed using the ORADUR® technology. J Appl Res. 2010; 10(3): 88-96.

Webster LR: PTI-821: Sustained-release oxycodone using gel-cap technology. Expert Opin Investig Drugs. 2007; 16(3): 359-366.

Lalovic B, Phillips B, Risler LL, et al.: Quantitative contribution of CYP2D6 and CYP3A to oxycodone metabolism in human liver and intestinal microsomes. Drug Metab Dispos. 2004; 32(4): 447-454.

Lalovic B, Kharasch E, Hoffer C, et al.: Pharmacokinetics and pharmacodynamics of oral oxycodone in healthy human subjects: Role of circulating active metabolites. Clin Pharmacol Ther. 2006; 79(5): 461-479.

Coluzzi F, Mattia C: Oxycodone. Pharmacological profile and clinical data in chronic pain management. Minerva Anestesiol. 2005; 71(7-8): 451-460.

Ordonez Gallego A, Gonzalez Baron M, Espinosa Arranz E: Oxycodone: A pharmacological and clinical review. Clin Transl Oncol. 2007; 9(5): 298-307.

Pugh RN, Murray-Lyon IM, Dawson JL, et al.: Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973; 60(8): 646-649.

US Food and Drug Administration Department of Health and Human Services: Guidance for Industry: Statistical Approaches to Establishing Bioequivalence. 2001. Available at http://www.fda.gov/downloads/Drugs/Guidances/ucm070244.pdf. Accessed August 10, 2014.

US Food and Drug Administration Department of Health and Human Services: Guidance for Industry: Bioavailability and Bioequivalence Studies for Orally Administered Drug Products—General Considerations. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070124.pdf. Accessed December 5, 2013.

Kirvela M, Lindgren L, Seppala T, et al.: The pharmacokinetics of oxycodone in uremic patients undergoing renal transplantation. J Clin Anesth. 1996; 8(1): 13-18.

Tallgren M, Olkkola KT, Seppala T, et al.: Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation. Clin Pharmacol Ther. 1997; 61(6): 655-661.

Villeneuve JP, Pichette V: Cytochrome P450 and liver diseases. Curr Drug Metab. 2004; 5(3): 273-282.