门诊手术患者可待因代谢过程中 CYP2D6 活性的群体药代动力学定量分析,以实现基于模型的精准用药。

IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Muhammad Waqar Ashraf, Satu Poikola, Mikko Neuvonen, Johanna I Kiiski, Vesa K Kontinen, Klaus T Olkkola, Janne T Backman, Mikko Niemi, Teijo I Saari
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引用次数: 0

摘要

背景和目的:由于多种细胞色素 P450(CYP)酶的参与,可待因在人体内的代谢非常复杂,而且有很强的遗传基础,这决定了相关 CYP450 酶在体内的表达水平。多态的 CYP2D6 可通过 O-去甲基化作用将可待因代谢为吗啡,而 CYP2D6 表型与可待因的阿片类药物不良反应之间的密切关联已得到充分证实。本研究旨在量化 CYP2D6 基因型对可待因生物转化的影响:我们对 1000 名患者进行了前瞻性临床试验,在试验过程中,非卧床患者术前服用 60 毫克可待因,并使用群体药代动力学模型量化了不同 CYP2D6 基因型的 CYP2D6 活性与吗啡暴露之间的关系。研究人员从 997 名患者处获得了可待因及其主要代谢物的血浆浓度数据,并对研究对象进行了 CYP2D6 基因型筛查,在建立模型时将每个 CYP2D6 等位基因的活性评分总和作为协变量:结果:我们的最终模型能够充分预测可待因的处置以及吗啡、可待因-6-葡萄糖醛酸苷和吗啡-3-葡萄糖醛酸苷的形成,同时考虑到了基于 CYP2D6 基因型的吗啡暴露差异。与之前的结果一致,功能减弱等位基因(CYP2D6*10 和 *41)患者的 CYP2D6 活性出现了不同程度的降低,这与活性评分的增加不一致。模型模拟表明,超快速 CYP2D6 代谢者体内的吗啡浓度达到了可能导致呼吸抑制的全身浓度(超过 9.1 纳克/毫升),与正常代谢者相比,吗啡暴露量高出 218%(19 对 8.7 微克-小时/升,p < 0.001)。同样,与正常代谢者相比,贫代谢者和中等代谢者的吗啡暴露量明显减少(1.0 和 3.7 对 8.7 µg - h/L,p < 0.001):我们的最终模型引领了在可待因治疗中实施以模型为依据的精确用药的方向,并将基因检测的使用确定为实施可待因合理药物治疗的一个不可或缺的组成部分。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Population Pharmacokinetic Quantification of CYP2D6 Activity in Codeine Metabolism in Ambulatory Surgical Patients for Model-Informed Precision Dosing.

Background and objective: Codeine metabolism in humans is complex due to the involvement of multiple cytochrome P450 (CYP) enzymes, and has a strong genetic underpinning, which determines the levels of relevant CYP450 enzyme expression in vivo. Polymorphic CYP2D6 metabolises codeine to morphine via O-demethylation, while a strong correlation between CYP2D6 phenotype and opioidergic adverse effects of codeine is well documented. The aim of this study was to quantify the effect of CYP2D6 genotype on the biotransformation of codeine.

Methods: We conducted a prospective clinical trial with 1000 patients, during which ambulatory patients were administered 60 mg of codeine preoperatively and the association between CYP2D6 activity and morphine exposure across various CYP2D6 genotypes was quantified using a population pharmacokinetic model. Plasma concentration data for codeine and its primary metabolites were obtained from 997 patients and CYP2D6 genotype was screened for study subjects, and respective sums of activity scores assigned for each CYP2D6 allele were used as covariates in model development.

Results: Our final model predicts the disposition of codeine and the formation of morphine, codeine-6-glucuronide and morphine-3-glucuronide adequately while accounting for variability in morphine exposure on the basis of CYP2D6 genotype. In agreement with previous results, patients with decreased function alleles (CYP2D6*10 and *41) showed varying levels of decrease in CYP2D6 activity that were inconsistent with increasing activity scores. Model simulations demonstrate that morphine concentrations in ultrarapid CYP2D6 metabolisers reach systemic concentrations that can potentially cause respiratory depression (over 9.1 ng/mL), and have 218% higher exposure (19 versus 8.7 µg · h/L, p < 0.001) to morphine than normal metabolisers. Similarly, poor and intermediate metabolisers had significantly reduced morphine exposure (1.0 and 3.7 versus 8.7 µg · h/L, p < 0.001) as compared with normal metabolisers.

Conclusions: Our final model leads the way in implementing model-informed precision dosing in codeine therapy and identifies the use of genetic testing as an integral component in the effort to implement rational pharmacotherapy with codeine.

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来源期刊
CiteScore
8.80
自引率
4.40%
发文量
86
审稿时长
6-12 weeks
期刊介绍: Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.
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