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PHARMACOKINETICS

Pharmacokinetics of Long-Acting Naltrexone in Subjects With Mild to Moderate Hepatic Impairment

Ryan Z. Turncliff, PhD, Joi L. Dunbar, PharmD, Qunming Dong, PhD, Bernard L. Silverman, MD, Elliot W. Ehrich, MD, Stacy C. Dilzer, RN and Kenneth C. Lasseter, MD

From Alkermes, Inc, Cambridge, Massachusetts (Dr Turncliff, Dr Dunbar, Dr Dong, Dr Silverman, Dr Ehrich) and SFBC International, Miami, Florida (Ms Dilzer, Dr Lasseter).

Long-acting naltrexone is an extended-release formulation developed with the goal of continuous naltrexone exposure for 1 month for the treatment of alcohol dependence. The influence of mild and moderate hepatic impairment on naltrexone pharmacokinetics following long-acting naltrexone 190-mg administration was assessed. Subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment (n = 6 per group) and matched control subjects (n = 13) were enrolled. Naltrexone and 6ß-naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6ß-naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC0-{infty}) of naltrexone and 6ß-naltrexol was similar across all groups. The long apparent half-lives of naltrexone and 6ß-naltrexol (5-8 days) were attributed to the slow release of naltrexone (long-acting naltrexone exhibits absorption rate-limited elimination or "flip-flop" kinetics); elimination was not altered in subjects with hepatic impairment. Based on pharmacokinetic considerations, the dose of long-acting naltrexone does not need to be adjusted in patients with mild or moderate hepatic impairment.

Key Words: Naltrexone • long acting • hepatic impairment • alcoholism • LA-NTX

Address for reprints: Ryan Z. Turncliff, PhD, Alkermes, Inc, 88 Sidney Street, Cambridge, MA 02139-4137; e-mail: Ryan.Turncliff{at}Alkermes.com.




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