Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
General Internal Medicine, Department of Medicine, Geneva University Hospitals, Geneva, Switzerland.
Clin Pharmacol Ther. 2022 Jun;111(6):1268-1277. doi: 10.1002/cpt.2576. Epub 2022 Mar 28.
Precision dosing strategies require accounting for between-patient variability in pharmacokinetics together with subsequent pharmacodynamic differences. Liquid biopsy is a valuable new approach to diagnose disease prior to the appearance of clinical signs and symptoms, potentially circumventing invasive tissue biopsies. However, the possibility of quantitative grading of biomarkers, as opposed to simply confirming their presence or absence, is relatively new. In this study, we aimed to verify expression measurements of cytochrome P450 (CYP) enzymes and the transporter P-glycoprotein (P-gp) in liquid biopsy against genotype and activity phenotype (assessed by the Geneva cocktail approach) in 30 acutely ill patients with cardiovascular disease in a hospital setting. After accounting for exosomal shedding, expression in liquid biopsy correlated with activity phenotype for CYP1A2, CYP2B6, CYP2C9, CYP3A, and P-gp (r = 0.44-0.70, P ≤ 0.05). Although genotype offered a degree of stratification, large variability (coefficient of variation (CV)) in activity (up to 157%) and expression in liquid biopsy (up to 117%) was observed within each genotype, indicating a mismatch between genotype and phenotype. Further, exosome screening revealed expression of 497 targets relevant to drug metabolism and disposition (159 enzymes and 336 transporters), as well as 20 molecular drug targets. Although there were no functional data available to correlate against these large-scale measurements, assessment of disease perturbation from healthy baseline was possible. Verification of liquid biopsy against activity phenotype is important to further individualize modeling approaches that aspire to achieve precision dosing from the start of drug treatment without the need for multiple rounds of dose optimization.
精准剂量策略需要考虑药代动力学的个体间变异性，以及随后的药效学差异。液体活检是一种有价值的新方法，可以在出现临床症状和体征之前诊断疾病，可能避免进行有创的组织活检。然而，定量分级生物标志物的可能性，而不是简单地确认它们的存在或不存在，相对较新。在这项研究中，我们旨在验证在医院环境中对 30 名患有心血管疾病的急危重症患者的液体活检中细胞色素 P450（CYP）酶和转运蛋白 P-糖蛋白（P-gp）的表达测量值与基因型和活性表型（通过日内瓦鸡尾酒方法评估）之间的相关性。在考虑外泌体脱落后，液体活检中的表达与 CYP1A2、CYP2B6、CYP2C9、CYP3A 和 P-gp 的活性表型相关（r = 0.44-0.70，P ≤ 0.05）。尽管基因型提供了一定程度的分层，但在每个基因型内观察到活性（高达 157%）和液体活检中的表达（高达 117%）的变异性很大（变异系数（CV）），表明基因型与表型之间不匹配。此外，外泌体筛选显示了与药物代谢和处置相关的 497 个靶标（159 个酶和 336 个转运蛋白）以及 20 个分子药物靶标的表达。虽然没有可用的功能数据来与这些大规模测量值相关联，但从健康基线评估疾病干扰是可能的。液体活检与活性表型的验证对于进一步个性化建模方法很重要，这些方法旨在从药物治疗开始就实现精准剂量，而无需多次进行剂量优化。
