Relevance of assessing drug concentration exposure in pharmacogenetic and imaging studies.
Relevance of assessing drug concentration exposure in pharmacogenetic and imaging studies.
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DOI：
10.1177/1359786806066044
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发表时间：
2006-07-01
期刊：
影响因子：
--
通讯作者：
Pollock, Bruce G
中科院分区：
文献类型：
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作者：
Lotrich, Francis E;Bies, Robert R;Pollock, Bruce G
如果没有药物浓度数据，很难解释药效学的差异。特别是，药物暴露的可变性可能会混淆对药物遗传学、治疗结果和神经成像研究的解释。由于依从性和药代动力学的不同，药物浓度的个体间变异性可能相当高。例如，清除率可能受到遗传、药物相互作用、年龄和疾病的影响。我们回顾了使用正电子发射断层扫描和神经内分泌测量对选择性5-羟色胺再摄取抑制剂的急性反应可以有浓度-反应关系的研究结果。我们还提出了初步证据，帕罗西汀的浓度-反应关系受到5-羟色胺转运体启动子上的基因差异的影响。在大型临床研究中，对药物暴露的准确评估可能是具有挑战性的，需要使用几种技术来评估暴露。群体药代动力学(Pop PK)是一种非常适合于分析大型试验的浓度数据的方法，因为每个患者只需少量的血浆样本就可以确定特定患者和群体参数。与依赖处方剂量或单谷水平相反，使用Pop PK更准确地确定暴露程度的能力减少了暴露可变性带来的异质性。POP PK分层贝叶斯方法在表征抗惊厥药物、抗生素、抗肿瘤药物和抗心律失常药物方面是有效的。我们最近成功地将这些POP PK分析纳入了选择性5-羟色胺再摄取抑制剂(SSRI)和第二代抗精神病药物的临床试验中对老年患者的常规评估。因此，对于神经成像、药物遗传学和行为研究的设计和解释，药物浓度暴露的评估是可行的，并且具有潜在的重要影响。
Pharmacodynamic differences are difficult to interpret without drug concentration data. In particular, variability in drug exposure may confound the interpretation of pharmacogenetic, therapeutic outcome, and neuroimaging studies. Inter-individual variability in concentrations can be quite high due to variable adherence and pharmacokinetics. For example, clearance may be influenced by genetics, drug interactions, age and illness. We review findings that acute responses to selective serotonin reuptake inhibitors can have a concentration-response relationship using positron emission tomography and neuroendocrine measures. We also present preliminary evidence that the concentration-response relationship for paroxetine is influenced by genotypic differences at the serotonin transporter promoter. In large clinical studies, the accurate assessment of drug exposure can be challenging, with several techniques used to assess exposure. Population pharmacokinetics (Pop PK) is a method that is ideally suited for analysing concentration data from large trials because both patient-specific and population parameters can be determined with only a small number of plasma samples per patient. As opposed to relying on prescribed doses or a single trough level, the ability to determine more accurately exposure with Pop PK reduces the heterogeneity introduced by exposure variability. Pop PK hierarchic Bayesian approaches have been effective for characterizing anticonvulsants, antibiotics, antineoplastics and antiarrhythmics. We have recently successfully incorporated these pop PK analyses into routine assessments of elderly patients in clinical trials of selective serotonin reuptake inhibitors (SSRIs) and second generation antipsychotics. For the design and interpretation of neuroimaging, pharmacogenetic, and behavioural studies, the assessment of drug concentration exposure is therefore feasible and has potentially important ramifications.