Selection of a hydrocodone bitartrate extended-release prototype with optimal tamper resistance and extended-release characteristics

Hydrocodone is available only in immediate-release (IR) combination products for treatment of pain in the United States. This randomized, open-label, crossover study intended to identify a prototype with the highest tamper resistance, which maintains optimal extended-release (ER) characteristics. Pharmacokinetic profiles were characterized for 3 ER hydrocodone prototypes designed to be resistant to rapid release of drug upon product tampering. After IRB approval and informed consent were obtained, healthy subjects were randomized. During the study, subjects received a single 45-mg dose of each of the 3 ER hydrocodone prototypes (with relatively low, intermediate, or high levels of OraGuard™ coating). There was a minimum 5-day washout between hydrocodone doses. Subjects received naltrexone before and after each dose of study medication to block opioid receptors and minimize opioid-related adverse events. Blood samples for pharmacokinetics were collected before and over 72 hours after each study drug administration. Measures included peak plasma concentration (C_max), time to C_max (t_max), area under the curve from time 0 to infinity (AUC_0-∞), and terminal elimination half-life (t_1/2). Safety also was assessed. Forty subjects enrolled; 37 completed the study. Mean values for the low-, intermediate-, and high-coating ER hydrocodone prototypes were: C_max, 49.2, 32.6, and 28.4 ng/mL; AUC_0-∞, 640.0, 600.3, and 577.8 ng•hr/mL; and t_1/2, 11.7, 11.4, and 11.3 hours, respectively. Median t_max values were 5.9, 7.9, and 8.5 hours, respectively. The incidence of adverse events was similar between the low- (16%), intermediate- (13%), and high-coating (24%) ER hydrocodone prototypes. No serious adverse events were reported. Each hydrocodone prototype demonstrated ER characteristics with plasma levels being maintained over the full intended 12-hour dosing interval. The high-coating ER hydrocodone prototype was selected for further development because of its potential to better resist rapid release of drug upon product tampering.