Optimizing Nortriptyline Dosing: A Comparison between Pharmacogenetics-Based, Phenotype-Based, and Standard Dosing.

Background and objective: 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.

Methods: 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 (χ²) tests. Variability in plasma concentrations was assessed using F-tests.

Results: Both pharmacogenetics-based (χ² (1) = 8.0, p = 0.01) and phenotype-based dosing (χ² (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 (χ² (1) = 0.33, p = 0.56).

Conclusions: 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.