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

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


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.


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

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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 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.



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