POPULATION PHARMACOKINETICS OF NORTRIPTYLINE DURING MONOTHERAPY AND DURING CONCOMITANT TREATMENT WITH DRUGS THAT INHIBIT CYP2D6 - AN EVALUATION WITH THE NONPARAMETRIC MAXIMUM-LIKELIHOOD METHOD

1 Therapeutic drug monitoring data for nortriptyline (674 analyses fro m 578 patients) were evaluated with the nonparametric maximum likeliho od (NPML) method in order to determine the population kinetic paramete rs of this drug and their relation to age, body weight and duration of treatment. 2 Clearance of nortriptyline during monotherapy exhibited a large interindividual variability and a skewed distribution. 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. This may be explained by the recent discovery of subjects with multiple copies of the gene encoding the cytochrome-P450-enzyme CYP2D6, which catalys es the hydroxylation of nortriptyline. However, erratic compliance wit h the prescription may also add to this finding. A separate distributi on of low clearance values with a frequency corresponding to that of p oor metabolizers of CYP2D6 (circa 7% in Caucasian populations) could n ot be detected. 3 Concomitant therapy with drugs that inhibit CYP2D6 r esulted in a major increase in the plasma nortriptyline concentrations . This was caused by a decrease in nortriptyline clearance, whereas th e volume of distribution was unchanged. 4 The demographic factors age and body weight had a minor influence on the clearance of nortriptylin e which was also unaffected by the duration of treatment.