Population pharmacokinetics of nortriptyline at monotherapy and during concomitant treatment with drugs that inhibit CYP2D6; an evaluation with the nonparametric maximum likelihood method

Markus Jerling(1) , Yann Merlé(2) , France Mentré(2) and Alain Mallet(2)

(1) Department of Clinical Pharmacology at the Karolinska Institute, Huddinge Hospital,

Therapeutic drug monitoring data of nortriptyline (NT) were evaluated with the nonparametric maximum likelihood method (NPML) in order to determine the population kinetic parameters of this drug and their relation to age, gender, body weight, treatment duration and concomitant treatment with drugs that inhibit the cytochrome P450-enzyme CYP2D6, the debrisoquine/sparteine hydroxylase. The activity of CYP2D6 is mainly genetically determined and displays a pronounced interindividual variability in the population. The NPML-method, which has no parametric restrictions, is especially aimed at describing such multimodal distributions. CYP2D6 catalyses the metabolism of NT and several other antidepressants and neuroleptics. It may become saturated at therapeutic concentrations of these drugs which explains the kinetic interactions seen during combination therapy.

Clearance of NT was found to be log-normally distributed during monotherapy. A small, separate fraction with a very high clearance, constituting between 0.5 % and 2 % of the population, was seen in both men and women. Subjects with multiple copies of the gene encoding CYP2D6, resulting in ultrarapid hydroxylation of drugs metabolized by this enzyme, have recently been discovered. Concomitant therapy with drugs that inhibit CYP2D6 resulted in significantly higher nortriptyline concentrations. This was caused by a decrease of the elimination rate constant, whereas the volume of distribution was unchanged. The covariates gender, age, body weight and the treatment duration explained very little of the interindividual variability in the clearance of NT.

The importance of the error model for the NPML-evaluation will be discussed and available techniques to determine the genetic influence on the metabolism of psychotropic drugs will be presented.

Reference: PAGE 3 () Abstr 866 [www.page-meeting.org/?abstract=866]

Poster: poster