Quantitative pharmacogenetics of nortriptyline - A novel approach

Objective: To quantitatively model nortriptyline clearance as a function of the cytochrome P450 (CYP) 2D6 genotype and to estimate the contribution of genotype to the interindividual variability in steady-state plasma concent ration and metabolic clearance. Design: Modelling study using data from two previously published studies. Participants: 20 healthy volunteers receiving single oral doses of nortript yline and 20 patients with depression on steady-state oral treatment. Methods: A total of 275 nortriptyline plasma concentrations were analysed b y standard nonlinear regression and nonlinear mixed effect models. The phar macokinetic model was a 1-compartment model with first order absorption and elimination. All participants had previously been genotyped with respect t o the CYP2D6 polymorphism. Results: A model in which the intrinsic clearance is a linear function of t he number of functional CYP2D6 genes and hepatic blood flow is fixed to 60 L/h gave the closest fit of the pharmacokinetic model to the data. Stable e stimates were obtained for population pharmacokinetic parameters and interi ndividual variances. Assuming 100% absorption, the model allows systemic cl earance and bioavailability to be estimated. Bioavailability was found to v ary between 0.17 and 0.71, depending on the genotype. Using the frequency d istribution of CYP2D6 genotype with the above results we estimate that, in compliant Swedish individuals on nortriptyline monotherapy, the number of f unctional CYP2D6 genes could explain 21% of the total interindividual varia nce in oral clearance of nortriptyline and 34% of that in steady-state plas ma concentrations. Conclusion: Nonlinear mixed-effects modelling can be used to quantify the i nfluence of the number of functional CYP2D6 genes on the metabolic clearanc e and plasma concentration of drugs metabolised by this enzyme. Gene dose h as a significant impact on drug pharmacokinetics and prior knowledge of it may aid in predicting plasma concentration of the drug and thus tailoring p atient-specific dosage regimens.