Clomipramine metabolism. Model-based analysis of variability factors from drug monitoring data

A steady-state model is here developed as a framework for the analysis of blood concentrations of clomipramine, obtained during routine drug monitoring. A model is proposed to account for its major metabolic pathways, hydroxylation and demethylation, including first-pass effect. Impaired hydroxylation capacity is shown to lead to a dramatic increase in the concentration of demethyl-clomipramine, with a concomitant moderate increase in that of the parent drug. Deficient demethylation capacity is associated with a reduced ratio of demethyl metabolite to parent drug. A nomogram is provided to allow easy determination of hydroxylation and demethylation capacities from routinely measured blood concentrations. Data from 150 patients are analysed in order to identify interindividual variability factors. Average pseudo-clearances, calculated from trough blood concentrations at steady-state, are 17 L/h for hydroxylation, 23 L/h for demethylation and 40 L/h for elimination of hydroxylated metabolites. Maximum to minimum ratios are 8, 27 and 11, respectively. The metabolising capacity through either process significantly decreases with increasing age, clearance estimates being 40 to 50% lower for patients 75 years or older than for those 40 years or younger. Tobacco smoking and chronic alcohol consumption induce and reduce the demethylation clearance, respectively. Inhibition of hydroxylation in the presence of phenothiazine comedication is also shown. Finally, small but significant differences according to sex are observed. Potential implications of the proposed model-based approach include adaptation of the dosage regimen to individual characteristics at the very beginning of antidepressant therapy, and early detection of patients with impaired metabolising capacities.