Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example
Integrating pharmacogenetics and therapeutic drug monitoring: optimal dosing of imatinib as a case-example
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DOI：
10.1007/s00228-009-0779-4
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发表时间：
2010-04-01
影响因子：
2.9
通讯作者：
Griffiths, Michael
中科院分区：
文献类型：
--
作者：
Li-Wan-Po, Alain;Farndon, Peter;Griffiths, Michael
为了说明药物遗传学与治疗药物监测的界面，估计伊马替尼治疗慢性髓性白血病的目标血药水平，通过文献综述为该界面的案例提供证据和必要的数据支持，并采用受试者工作曲线（ROC；信号检测理论）分析对数据进行定量分析，估计伊马替尼的目标血药水平。一项研究通过ROC分析估计伊马替尼治疗慢性髓性白血病的最佳靶水平为1002 ng/mL （1.70 A μ M）。使用另一项研究中报告的个体患者水平数据和相同的方法，我们估计目标水平为0.95 μ m。这与其他观察性研究的结果一致，这些研究的剂量反应不是主要研究目标。现有证据表明，剂量-血水平反应存在相当大的个体差异。除了代谢酶和转运体的药物遗传学外，参与信号通路的基因的基因突变也可能解释剂量-血液水平和剂量-临床反应关系中广泛的个体间差异。对于所有符合药理学条件的患者，单剂量方案并不是给慢性髓性白血病患者开伊马替尼的最佳策略。我们建议，治疗药物监测旨在确保1 a μ M的低谷目标水平，以减少假性耐药的发生率，从而个性化治疗并优化对伊马替尼的反应。然后可以进一步探究其他原因的持续耐药性。
To illustrate the interface of pharmacogenetics and therapeutic drug monitoring and to estimate target blood level for imatinib in the treatment of chronic myelogenous leukemiaA literature review to provide the evidence and necessary data to support the case for the interface, and quantitative analysis of the data to estimate the target blood level for imatinib using receiver operating curve (ROC; signal detection theory) analysis.One study estimated the optimum target level of imatinib in chronic myelogenous leukaemia as 1002 ng/mL (1.70 A mu M) through ROC analysis. Using individual-patient level data reported in another study and the same methodology, we estimated the target level as 0.95 A mu M. This is consistent with the results of other observational studies where dose-response was not the primary research objective. The available evidence suggests considerable inter-individual variability in dose-blood level response. In addition to the pharmacogenetics of metabolic enzymes and transporters, genetic mutations in genes participating in the signalling pathways may also account for the wide inter-individual variability in dose-blood level and dose-clinical response relationships.A single-dose regimen for all pharmacogenetically eligible patients is not the optimum strategy for prescribing imatinib to patients with chronic myelogenous leukaemia. We suggest that therapeutic drug monitoring aimed at ensuring a trough target level of 1 A mu M would reduce the incidence of pseudo-resistance and hence personalize treatment and optimise response to imatinib. Persistent resistance can then be probed further for other causes.