Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials.
Population Pharmacokinetics of a Monthly Buprenorphine Depot Injection for the Treatment of Opioid Use Disorder: A Combined Analysis of Phase II and Phase III Trials.
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每月丁丙诺啡仓库注射阿片类药物使用障碍的人群药代动力学：II期和III期试验的组合分析。
DOI：
10.1007/s40262-020-00957-0
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发表时间：
2021-04
影响因子：
4.5
通讯作者：
Laffont CM
中科院分区：
文献类型：
--
作者：
Jones AK;Ngaimisi E;Gopalakrishnan M;Young MA;Laffont CM
BUP-XR（又名 RBP-6000 或 SUBLOCADE™）是一种缓释皮下注射丁丙诺啡制剂，用于治疗阿片类药物使用障碍。 BUP-XR 的设计目的是在整个每月给药间隔内提供持续的丁丙诺啡暴露，浓度足以控制疾病的各个方面（戒断、渴望和阻断阿片类药物的主观效应）。根据 II 期和 III 期数据表征 BUP-XR 的群体药代动力学，并评估 III 期计划中评估的给药方案是否达到目标治疗浓度。群体药代动力学分析包括 570 名患有阿片类药物使用障碍的受试者，他们在舌下含服丁丙诺啡诱导后接受长达 12 个月的 BUP-XR 注射。在 III 期研究中，丁丙诺啡的目标治疗浓度从第一次注射起就达到了，并在整个治疗期间得以维持。丁丙诺啡血浆浓度-时间曲线通过二室模型得到了很好的描述，其中舌下丁丙诺啡的一级吸收和 BUP-XR 的双吸收子模型。协变量分析评估了受试者的人口特征、实验室数据和遗传状态对丁丙诺啡代谢酶的影响。最终模型中仅保留了两个协变量：体重指数和体重。总体而言，它们的影响不足以证明剂量调整的合理性。最后，药代动力学模拟表明，丁丙诺啡血浆浓度在停止治疗后缓慢下降，并且偶尔延迟给药 2 周不会影响疗效，这转化为标签声明。总之，本分析导致了稳健的群体药代动力学模型的开发，并证实了 BUP-XR 在整个治疗期间输送和维持治疗血浆浓度的能力。本文的在线版本 (10.1007/s40262-020-00957-0) 包含补充材料，可供授权用户使用。
BUP-XR (a.k.a. RBP-6000 or SUBLOCADE™) is an extended-release subcutaneous buprenorphine formulation for the treatment of opioid use disorder. BUP-XR was designed to provide sustained buprenorphine exposure throughout the monthly dosing interval, at concentrations sufficient to control all aspects of the disease (withdrawal, craving, and blockade of opioid subjective effects). To characterize the population pharmacokinetics of BUP-XR based on phase II and phase III data and to evaluate whether target therapeutic concentrations were reached with the dosing regimens evaluated in the phase III program. The population pharmacokinetic analysis included 570 subjects with opioid use disorder who received up to 12 monthly BUP-XR injections following induction with sublingual buprenorphine. In phase III studies, target therapeutic concentrations of buprenorphine were achieved from the first injection and maintained over the entire treatment duration. Buprenorphine plasma concentration–time profiles were well described by a two-compartment model, with first-order absorption for sublingual buprenorphine and a dual absorption submodel for BUP-XR. A covariate analysis evaluated the effects of subjects’ demographic characteristics, laboratory data, and genetic status regarding buprenorphine-metabolizing enzymes. Only two covariates, body mass index and body weight, were retained in the final model. Overall, their effects were not of sufficient magnitude to justify a dose adjustment. Finally, pharmacokinetic simulations showed that buprenorphine plasma concentrations decreased slowly after discontinuation of treatment and that a 2-week occasional delay in dosing would not impact efficacy, which translated into labeling claims. In conclusion, the present analysis led to the development of a robust population pharmacokinetic model and confirms the ability of BUP-XR to deliver and maintain therapeutic plasma concentrations over the entire treatment duration. The online version of this article (10.1007/s40262-020-00957-0) contains supplementary material, which is available to authorized users.
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影响因子：
2.9
作者：
Nasser AF;Greenwald MK;Vince B;Fudala PJ;Twumasi-Ankrah P;Liu Y;Jones JP 3rd;Heidbreder C
通讯作者：
Heidbreder C
影响因子：
6.1
作者：
Lindbom, L;Pihlgren, P;Jonsson, N
通讯作者：
Jonsson, N
影响因子：
3.9
作者：
Reimer, Jens;Wright, Nat;D'Agnone, Oscar
通讯作者：
D'Agnone, Oscar
影响因子：
2.9
作者：
Andorn, Anne C.;Haight, Barbara R.;Rutrick, Daniel
通讯作者：
Rutrick, Daniel
影响因子：
10.6
作者：
Greenwald, Mark;Johanson, Chris-Ellyn;Zubieta, Jon-Kar
通讯作者：
Zubieta, Jon-Kar