Potential for Precision Medicine in Methadone Treatment of Opioid Use Disorder.
Potential for Precision Medicine in Methadone Treatment of Opioid Use Disorder.
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美沙酮治疗阿片类药物使用障碍的精准医学潜力。
DOI：
10.1097/adm.0000000000000619
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发表时间：
2020
影响因子：
5.5
通讯作者：
Saxon,AndrewJ
中科院分区：
文献类型：
--
作者：
Saxon,AndrewJ
McCarthy 等人 (2020) 的论文为将精准医学应用于使用美沙酮治疗阿片类药物使用障碍 (OUD) 开辟了潜在的新机会。 McCarthy 及其同事分析了接受美沙酮 OUD 维持治疗的患者提供的 1700 份血液样本的数据，并将其发送到单一临床实验室进行血清美沙酮浓度测定。该分析发现，血清美沙酮浓度与其无活性代谢物乙啶二甲基二苯吡咯烷 (EDDP) 浓度的比率可用于将样品分为 4 类，与药代动力学文献中经典定义的 4 类代谢活性密切对应，以描述给定药理化合物的人体代谢变化： 代谢不良者 （论文中称为超慢代谢者）、中间代谢者、粗代谢者、超快代谢者。分析进一步表明，这些类别与美沙酮血清浓度峰谷比之间存在显着相关性，这种相关性已经得到了临床认可，并且是在患者对美沙酮反应不佳时获得的，特别是当患者抱怨服药前戒断症状时，无论每日剂量有多高。具有这种临床特征且峰谷比大于 2 的患者被认为是粗代谢或超快速代谢者，其中美沙酮的半衰期较短，因此需要分次给药，将每日总剂量分为 2 次单独给药，以保持血清谷浓度高于出现戒断症状的范围。作为背景，正如 McCarthy 等人简要指出的那样，美沙酮的代谢相当复杂，尚未完全阐明。目前的理解表明，多种 CYP 450 酶系统，包括 CYP3A4、CYP2B6、CYP2C19、CYP2D6、CYP2C9 和 CYP2C8，可能有助于美沙酮 N-去甲基化为 EDDP，因此不同个体的代谢途径可能不同 (Volpe et al., 2018)。 CYP 450 酶活性主要由遗传决定，环境影响也有一定贡献，例如各种底物的酶抑制或诱导。了解遗传对美沙酮代谢影响的科学仍处于起步阶段，但初步数据表明，CYP2B6 的多态性确实可能有助于代谢率，而 CYP2D6 的多态性似乎没有这种作用（Victorri-Vigneau 等人，2019）。当人们考虑到所涉及的过多酶、可能导致美沙酮代谢改变的潜在多态性数量，以及单个个体中不同遗传影响之间的潜在相互作用时，似乎很明显，目前还没有进行临床上有用的基因测试，将接受美沙酮的患者分为上述 4 个代谢组中的一组。因此，一种可以起到类似功能的更简单的生物标志物，例如麦卡锡等人提出的美沙酮/EDDP比率，具有相当大的吸引力。这样的生物标志物可以提供哪些临床优势？ McCarthy 等人指出，据我们目前所知，在接受美沙酮 OUD 治疗的人群中，粗代谢和超快速代谢者最多占 10% 左右。因此，在持续的常规临床护理过程中，绝大多数患者无需获得血清美沙酮水平或任何其他生物标志物，只需使用临床判断即可在出现戒断症状时确定治疗美沙酮剂量……
T he paper by McCarthy et al.(2020) opens a potential new opportunity to apply precision medicine to the use of methadone to treat opioid use disorder (OUD). McCarthy and colleagues analyzed data from 1700 blood specimens provided by patients receiving methadone maintenance treatment for OUD and sent to a single clinical laboratory for assays of serum methadone concentrations. This analysis found that the ratio of serum methadone concentration to the concentration of its inactive metabolite ethylidine-dimethyl-diphenypyrrolidine (EDDP) could be used to divide the samples into 4 categories closely corresponding to the 4 categories of metabolic activity classically defined in the pharmacokinetic literature to describe the human variation in metabolism of a given pharmacologic compound: poor metabolizers (called ultra-slow metabolizers in the paper), intermediate metabolizers, extensive metabolizers, and ultra-rapid metabolizers. The analysis further showed significant associations between these categories and the methadone serum concentration peak to trough ratio which already has recognized clinical utility and is obtained when patients demonstrate a poor response to methadone, particularly when patients complain of pre-dose withdrawal symptoms no matter how high the daily dosage goes. Patients with this clinical profile and a peak to trough ratio greater than 2 are presumed to be extensive or ultra-rapid metabolizers in whom methadone has a short half-life, and who will therefore require split dosing, having their total daily dosage divided into 2 separate administrations, to keep the trough serum level above the range at which withdrawal symptoms supervene. For background and as briefly noted by McCarthy et al, the metabolism of methadone is quite complex and not yet fully elucidated. Current understanding indicates that multiple CYP 450 enzyme systems, including CYP3A4, CYP2B6, CYP2C19, CYP2D6, CYP2C9, and CYP2C8, likely contribute to N-demethylation of methadone to EDDP, and so metabolic pathways might be different across different individuals (Volpe et al., 2018). CYP 450 enzyme activities are determined largely by genetics with some contribution by environmental effects, for example enzyme inhibition or induction by various substrates. The science of understanding genetic effects on methadone metabolism remains in its infancy, but preliminary data suggest that polymorphisms in CYP2B6 may indeed contribute to rate of metabolism, whereas polymorphisms in CYP2D6 appear not to do so (Victorri-Vigneau et al., 2019). When one considers the plethora of enzymes involved, the number of potential polymorphisms that could contribute to alterations in methadone metabolism, and the potential interactions between different genetic influences in a single individual, it seems quite apparent that clinically useful genetic testing to place patients receiving methadone in 1 of 4 metabolizer groups described above is not on the current horizon. Thus, a simpler biomarker that could serve a similar function, such as the methadone/EDDP ratio propounded by McCarthy et al, holds considerable allure.What clinical advantages might such a biomarker offer? McCarthy et al point out that, to the best of our current awareness, extensive and ultra-rapid metabolizers make up at most about 10% of the population of individuals receiving methadone treatment for OUD. Thus, during ongoing routine clinical care the vast majority of patients can be well managed without obtaining serum methadone levels or any other biomarker and simply using clinical judgment to determine a therapeutic methadone dosage when withdrawal signs …
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