Dunbar Joi L, Turncliff Ryan Z, Dong Qunming, Silverman Bernard L, Ehrich Elliot W, Lasseter Kenneth C
Alkermes Inc, Cambridge, MA 02139, USA.
Alcohol Clin Exp Res. 2006 Mar;30(3):480-90. doi: 10.1111/j.1530-0277.2006.00052.x.
Oral naltrexone is effective in the treatment of alcohol dependence; however, a major limitation of its clinical utility is poor patient adherence to the daily dosing schedule. A biodegradable, long-acting naltrexone microsphere formulation was developed to achieve continuous naltrexone exposure for 1 month in the treatment of alcohol dependence.
The single- and multiple-dose safety and pharmacokinetics of a long-acting naltrexone microsphere preparation were evaluated in healthy subjects. One group of subjects (n = 28) received a single dose of oral naltrexone 50 mg followed by a single gluteal intramuscular (IM) injection of long-acting naltrexone 190 or 380 mg or placebo. A different group of subjects (n = 14) received oral naltrexone 50 mg daily for 5 days, followed by IM long-acting naltrexone 380 mg or placebo every 28 days for a total of 4 doses. A 7-day washout period separated oral and IM administrations. Blood samples were collected to determine plasma concentrations of naltrexone and the primary metabolite, 6beta-naltrexol.
After a single IM injection of long-acting naltrexone 380 mg, naltrexone plasma concentrations were measurable in all subjects for at least 31 days postdose. The pharmacokinetics were proportional to the dose and multiple dose observations were consistent with single dose observations. Mean apparent elimination half-lives for naltrexone and 6beta-naltrexol ranged from 5 to 7 days. Exposure to 6beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred.
This study demonstrated that the long-acting naltrexone formulation was well tolerated, displayed predictable pharmacokinetics, and resulted in no meaningful drug accumulation upon multiple dosing. Intramuscular administration avoids first-pass metabolism and changes the exposure ratio of 6beta-naltrexol to naltrexone compared with oral administration. By providing continuous exposure to naltrexone for several weeks following IM injection, this long-acting naltrexone formulation may offer therapeutic benefit to those patients who experience difficulty adhering to the daily administration schedule necessitated by oral naltrexone therapy.
口服纳曲酮对酒精依赖的治疗有效；然而，其临床应用的一个主要局限是患者对每日给药方案的依从性差。为了在酒精依赖治疗中实现纳曲酮持续暴露1个月，研发了一种可生物降解的长效纳曲酮微球制剂。
在健康受试者中评估了长效纳曲酮微球制剂的单剂量和多剂量安全性及药代动力学。一组受试者（n = 28）接受50 mg口服纳曲酮单剂量，随后单次臀肌肌内注射190 mg或380 mg长效纳曲酮或安慰剂。另一组受试者（n = 14）连续5天每日接受50 mg口服纳曲酮，随后每28天接受380 mg长效纳曲酮或安慰剂肌内注射，共4剂。口服和肌内注射之间有7天的洗脱期。采集血样以测定纳曲酮及其主要代谢物6β-纳曲醇的血浆浓度。
单次肌内注射380 mg长效纳曲酮后，所有受试者给药后至少31天可测得纳曲酮血浆浓度。药代动力学与剂量成正比，多剂量观察结果与单剂量观察结果一致。纳曲酮和6β-纳曲醇的平均表观消除半衰期为5至7天。与口服给药相比，肌内注射后6β-纳曲醇的暴露量减少。未发生严重不良事件。
本研究表明，长效纳曲酮制剂耐受性良好，药代动力学可预测，多次给药后无明显药物蓄积。与口服给药相比，肌内注射避免了首过代谢，并改变了6β-纳曲醇与纳曲酮的暴露比例。通过肌内注射后数周持续暴露于纳曲酮，这种长效纳曲酮制剂可能对那些难以坚持口服纳曲酮治疗所需每日给药方案的患者具有治疗益处。
