Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone
Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone
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DOI：
10.1111/j.1530-0277.2006.00052.x
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发表时间：
2006-03-01
影响因子：
3.2
通讯作者：
Lasseter, KC
中科院分区：
文献类型：
--
作者：
Dunbar, JL;Turncliff, RZ;Lasseter, KC
背景：口服纳曲酮治疗酒精依赖是有效的；然而，其临床应用的一个主要限制是患者对每日给药计划的依从性差。开发了一种可生物降解的长效纳曲酮微球制剂，以实现连续1个月的纳曲酮暴露治疗酒精依赖。方法：对一种长效纳曲酮微球制剂进行单剂量和多剂量安全性及药代动力学评价。一组受试者（n = 28）接受单剂量口服纳曲酮50 mg，随后单次臀肌内注射长效纳曲酮190或380 mg或安慰剂。另一组受试者（n = 14）每天口服纳曲酮50mg，连续5天，随后每28天口服长效纳曲酮380mg或安慰剂，共4次剂量。7天的洗脱期将口服和IM药物分开。采集血液样本，测定纳曲酮及其主要代谢物6 -纳曲醇的血浆浓度。结果：单次IM注射长效纳曲酮380 mg后，所有受试者的纳曲酮血药浓度在给药后至少31天内均可测量。药代动力学与剂量成正比，多次给药观察结果与单次给药观察结果一致。纳曲酮和6 -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，IM注射减少了6 -纳曲醇的暴露。未发生严重不良事件。结论：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，多次给药无明显药物积累。与口服给药相比，肌内给药避免了首过代谢，改变了6 -纳曲醇对纳曲酮的暴露率。通过在注射IM后持续暴露于纳曲酮数周，这种长效纳曲酮制剂可能为那些难以坚持口服纳曲酮治疗所需的每日给药计划的患者提供治疗益处。
Background: 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.Methods: 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, 6 beta-naltrexol.Results: 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 6 beta-naltrexol ranged from 5 to 7 days. Exposure to 6 beta-naltrexol was reduced with IM injection compared with that oral administration. No serious adverse events occurred.Conclusions: 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 6 beta-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.