Vos Cornelis F, Coenen Marieke J H, Ter Hark Sophie E, Schellekens Arnt F A, Aarnoutse Rob E, Janzing Joost G E, Ter Heine Rob
Department of Psychiatry, Radboud University Medical Center, Reinier Postlaan 10, 6526 GC, Nijmegen, The Netherlands.
Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
Clin Pharmacokinet. 2025 May 25. doi: 10.1007/s40262-025-01528-x.
Nortriptyline, a tricyclic antidepressant, has an important role in the pharmacotherapy of major depressive disorder (MDD). Individualized dosing approaches, such as pharmacogenetics-based and phenotype-based dosing, may enhance early achievement of therapeutic plasma concentrations, but their comparative accuracy has not been investigated. Our objective was to compare the accuracy of three nortriptyline dosing strategies: pharmacogenetics-based, phenotype-based, and standard dosing.
Using pharmacokinetic modeling based on data from a randomized controlled trial, we assessed and compared the following dosing strategies: pharmacogenetics-based dosing depending on the cytochrome P-450 (CYP) 2D6 genotype, phenotype-based dosing determined by the plasma concentration measured after a single nortriptyline administration, and standard dosing (125 mg/day). A population pharmacokinetic model was developed to assess phenotype-based dosing recommendations. We evaluated the dosing strategies by comparing the number of participants with predicted therapeutic, subtherapeutic, and supratherapeutic plasma concentrations using Chi-squared (χ) tests. Variability in plasma concentrations was assessed using F-tests.
Both pharmacogenetics-based (χ (1) = 8.0, p = 0.01) and phenotype-based dosing (χ (1) = 5.3, p = 0.02) significantly increased the likelihood of achieving therapeutic plasma concentrations compared with standard dosing while reducing plasma concentration variability. No significant difference was found in the prediction of therapeutic concentrations between the two individualized dosing strategies (χ (1) = 0.33, p = 0.56).
Pharmacogenetics-based and phenotype-based dosing demonstrate greater accuracy in predicting therapeutic nortriptyline plasma concentrations than standard dosing. Further research is warranted to explore the clinical application of model-informed precision dosing for nortriptyline and other psychotropic medications.
去甲替林作为一种三环类抗抑郁药，在重度抑郁症（MDD）的药物治疗中发挥着重要作用。个体化给药方法，如基于药物遗传学和基于表型的给药，可能会提高治疗性血浆浓度的早期达成率，但其相对准确性尚未得到研究。我们的目的是比较三种去甲替林给药策略的准确性：基于药物遗传学的给药、基于表型的给药和标准给药。
利用基于一项随机对照试验数据的药代动力学模型，我们评估并比较了以下给药策略：基于细胞色素P - 450（CYP）2D6基因型的基于药物遗传学的给药、单次服用去甲替林后测得的血浆浓度所确定的基于表型的给药，以及标准给药（125毫克/天）。建立了群体药代动力学模型以评估基于表型的给药建议。我们通过使用卡方（χ）检验比较达到预测治疗性、亚治疗性和超治疗性血浆浓度的参与者数量来评估给药策略。使用F检验评估血浆浓度的变异性。
与标准给药相比，基于药物遗传学的给药（χ（1）= 8.0，p = 0.01）和基于表型的给药（χ（1）= 5.3，p = 0.02）均显著增加了达到治疗性血浆浓度的可能性，同时降低了血浆浓度变异性。两种个体化给药策略在治疗浓度预测方面未发现显著差异（χ（1）= 0.33，p = 0.56）。
基于药物遗传学的给药和基于表型的给药在预测去甲替林治疗性血浆浓度方面比标准给药具有更高的准确性。有必要进一步研究探索模型指导的精准给药在去甲替林和其他精神药物临床应用中的情况。
