A pharmacokinetic evaluation of single and multiple doses of extended-release hydrocodone bitartrate in subjects experiencing surgical or osteoarthritic pain

Authors

  • Cynthia Y. Robinson, PhD
  • Christopher M. Rubino, PharmD
  • Stephen J. Farr, PhD

DOI:

https://doi.org/10.5055/jom.2015.0290

Keywords:

extended-release formulation, hydrocodone, pharmacokinetics, dose-proportionality

Abstract

Objectives: To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies.

Setting: Both studies were multicenter clinical studies.

Subjects and interventions: In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone-ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites.

Main outcome measures: Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods.

Results: Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steady-state mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies.

Conclusions: The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval.

Author Biographies

Cynthia Y. Robinson, PhD

Senior Scientific Advisor, Clinical Development, Zogenix, Inc., San Diego, California.

 

Christopher M. Rubino, PharmD

Vice President, Pharmacometrics, Institute for Clinical Pharmacodynamics, Latham, New York; Adjunct Assistant Research Professor, School of Pharmacy and Pharmaceutical Sciences, SUNY University at Buffalo, Buffalo, New York.

Stephen J. Farr, PhD

President, Zogenix, Inc., Emeryville, California

References

Yaksh TL, Wallace MS: Opioids, analgesia and pain management. In Brunton LL, Chabner BA, Knollmann BC (eds.):

Goodman and Gilman's the Pharmacological Basis of Therapeutics. 12th ed. New York, NY: McGraw-Hill, 2011: 481-525.

US Food and Drug Administration: FDA provides facts about Zohydro. Available at http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm395456.htm. Accessed May 29, 2014.

Arundel C, Lewis JH: Drug-induced liver disease in 2006. Curr Opin Gastroenterol. 2007; 23(3): 244-254.

Amar PJ, Schiff ER: Acetaminophen safety and hepatotoxicity—Where do we go from here? Expert Opin Drug Safety. 2007; 6(4): 341-355.

Blieden M, Paramore LC, Shah D, et al.: A perspective on the epidemiology of acetaminophen exposure and toxicity in the United States. Expert Rev Clin Pharmacol. 2014; 7(3): 341-348.

Roth SH, Fleischmann RM, Burch FX, et al.: Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain. Arch Intern Med. 2000; 160(6): 853-860.

Rauck RL, Nalamachu S, Wild JE, et al.: Single-entity hydrocodone extended-release capsules in opioid-tolerant subjects with moderate-to-severe chronic low back pain: a randomized double-blind, placebo-controlled study. Pain Med. 2014; 15(6): 975-985.

Wallace M, Thipphawong J: Open-label study on the long-term efficacy, safety, and impact on quality of life of OROS hydromorphone ER in patients with chronic low back pain. Pain Med. 2010; 11(10): 1477-1488.

Miller K, Yarlas A, Wen W, et al.: Buprenorphine transdermal system and quality of life in opioid-experienced patients with chronic low back pain. Expert Opin Pharmacother. 2013; 14(3): 269-277.

Yarlas A, Miller K, Wen W, et al.: A randomized, placebo-controlled study of the impact of the 7-day buprenorphine transdermal system on health-related quality of life in opioid-naïve patients with moderate-to-severe chronic low back pain. J Pain. 2013; 14(1): 14-23.

Zogenix: Zohydro® ER (hydrocodone bitartrate) extendedr-elease capsules, for oral use, CII [prescribing information]. San Diego, CA: Zogenix, Inc., January 2015.

Rubino C, Robinson CY, Smith EF: Data on File. Morristown, NJ: Pernix Therapeutics, 2011.

Melhem MR, Rubino CM, Farr SJ, et al.: Population pharmacokinetic analysis for hydrocodone following the administration of hydrocodone bitartrate extended-release capsules. Clin Pharmacokinet. 2013; 52(10): 907-917.

Navani DM, Yoburn BC: In vivo activity of norhydrocodone: An active metabolite of hydrocodone. J Pharmacol Exp Ther. 2013; 347(2): 497-505.

Hennies HH, Friderichs E, Schneider J: Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids. Arzneimittelforschung. 1988; 38(7): 877-880.

Chen ZR, Irvine RJ, Somogyi AA, et al.: Mu receptor binding of some commonly used opioids and their metabolites. Life Sci. 1991; 48(22): 2165-2171.

Otton SV, Schadel M, Cheung SW, et al.: CYP2D6 phenotype determines the metabolic conversion of hydrocodone to hydromorphone. Clin Pharmacol Ther. 1993; 54(5): 463-472.

Kaplan HL, Busto UE, Baylon GJ, et al.: Inhibition of cytochrome P450 2D6 metabolism of hydrocodone to hydromorphone does not importantly affect abuse liability. J Pharmacol Exp Ther. 1997; 281(1): 103-108.

Zhou K, Khokhar JY, Zhao B, et al.: First demonstration that brain CYP2D-mediated opiate metabolic activation alters analgesia in vivo. Biochem Pharmacol. 2013; 85(12): 1848-1855.

Llerena A, Naranjo ME, Rodrigues-Soares F, et al.: Interethnic variability of CYP2D6 alleles and of predicted and measured metabolic phenotypes across world populations. Expert Opin Drug Metabol Toxicol. 2014; 10(11): 1569-1583.

Ellis DJ, Farr SJ: Steady-state pharmacokinetics and safety of single-entity hydrocodone extended release in subjects with osteoarthritis pain [Poster 467]. Presented at the American Pain Society's 32nd Annual Scientific Meeting, New Orleans, LA, May 8-11, 2013.

Published

09/01/2015

How to Cite

Robinson, PhD, C. Y., C. M. Rubino, PharmD, and S. J. Farr, PhD. “A Pharmacokinetic Evaluation of Single and Multiple Doses of Extended-Release Hydrocodone Bitartrate in Subjects Experiencing Surgical or Osteoarthritic Pain”. Journal of Opioid Management, vol. 11, no. 5, Sept. 2015, pp. 405-1, doi:10.5055/jom.2015.0290.