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

doi:10.5055/jom.2015.0290

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

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