Pharmacokinetics of hydrocodone following administration of single and multiple 90-mg doses of extended-release hydrocodone bitartrate formulated with OraGuard™ technology

Abstract

A novel extended-release hydrocodone tablet, formulated with OraGuard™ technology, is being developed. This study evaluated the pharmacokinetics and tolerability of single and multiple doses of 90 mg in healthy, naltrexone-blocked subjects. After IRB approval and written informed consent were obtained, subjects received a 90-mg dose in Period 1 (single dose). In Period 2 (multiple doses every 12 hours), subjects were titrated from 45 mg to 90 mg over 5 days then continued on 90 mg until day 10. Subjects also received 50-mg naltrexone every 12 hours. Plasma samples were collected before and over 72 hours after each study drug administration. Pharmacokinetic parameters included peak plasma drug concentration (Cmax), area under the curve (AUC) from time 0 to the time of last measurable drug concentration (AUC0-t), AUC from time 0 to 12 hours after a single dose (AUC0-12), AUC for 1 dosing interval after multiple doses (AUCτ), terminal elimination half-life (t1/2), and observed (Robs) and steady-state accumulation (Rss) ratios. Tolerability also was assessed. Thirty-three of 40 enrolled subjects completed the study. Mean values after single and multiple doses were: Cmax 56.4 and 123.1 ng/mL, AUC0-t 1064 and 2453 ng•h/mL, and t1/2 9.9 and 10.7 hours, respectively. Mean AUC0-12 after a single dose was 462 ng•h/mL, and mean AUCτ after multiple doses was 1282 ng•h/mL. Mean Robs was 2.8 and mean Rss was 1.2. No serious adverse events were reported. Five subjects discontinued due to adverse events. The pharmacokinetic profile of hydrocodone was qualitatively similar after single and multiple 90-mg doses and is consistent with that observed after multiple dosing of 45 mg every 12 hours in a previous study. Mean hydrocodone exposure was 2.8-fold higher at steady state than after a single dose. Extended-release hydrocodone was well tolerated by the naltrexone-blocked subjects in this study.