Turncliff Ryan Z, Dunbar Joi L, Dong Qunming, Silverman Bernard L, Ehrich Elliot W, Dilzer Stacy C, Lasseter Kenneth C
Alkermes, Inc, 88 Sidney Street, Cambridge, MA 02139-4137, USA.
J Clin Pharmacol. 2005 Nov;45(11):1259-67. doi: 10.1177/0091270005280199.
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 6beta-naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6beta-naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC(0-infinity)) of naltrexone and 6beta-naltrexol was similar across all groups. The long apparent half-lives of naltrexone and 6beta-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.
长效纳曲酮是一种缓释制剂，其研发目的是使纳曲酮持续暴露1个月，用于治疗酒精依赖。评估了轻度和中度肝功能损害对长效纳曲酮190mg给药后纳曲酮药代动力学的影响。纳入了轻度（Child-Pugh A级）和中度（Child-Pugh B级）肝功能损害的受试者（每组n = 6）以及匹配的对照受试者（n = 13）。在单次肌内注射后63天内测定纳曲酮和6β-纳曲醇浓度。在所有受试者中均检测到纳曲酮和6β-纳曲醇浓度直至28天。所有组中纳曲酮和6β-纳曲醇的总暴露量（AUC(0-∞)）相似。纳曲酮和6β-纳曲醇的长表观半衰期（5-8天）归因于纳曲酮的缓慢释放（长效纳曲酮表现出吸收速率限制消除或“翻转”动力学）；肝功能损害受试者的消除未改变。基于药代动力学考虑，轻度或中度肝功能损害患者的长效纳曲酮剂量无需调整。
