Population Pharmacokinetics of Clomipramine, Desmethylclomipramine, and Hydroxylated Metabolites in Patients With Depression Receiving Chronic Treatment: Model Evaluation

Abstract

Because metabolites play a major role in the clinical response to clomipramine, the objective of the current study was to develop a population model and evaluate its performance to describe the pharmacokinetic profiles of clomipramine (C) and its active metabolites desmethylclomipramine (DC), 8-hydroxy-clomipramine (OHC) and 8-hydroxy-desmethylclomipramine (OHDC). A first sample of 14 patients served for development of a 2-molecule C and DC model, which was shown to provide reasonable estimates of AUC-based clearances, as well as precise estimation of interindividual variability. Simulated data, generated to mimic a semi-rich sampling design and chronic treatment with clomipramine, indicated that clearance estimation was feasible under routine treatment conditions. A second sample of 30 patients, recruited prospectively and followed for a median 4-week period, was used to extend the 2-molecule model to a 4-molecule model. Goodness-of-fit assessment revealed that model-predicted concentrations were reasonably close to observed concentrations for a majority of patients. Interindividual variability was 50% to 60% for hydroxylation and desmethylation clearances, and residual variability was 30%. The proposed model incorporates much of what is known about the metabolism of clomipramine and may valuably integrate the influence of genetic and environmental factors on each metabolic pathway.

Pharmacokinetics of clomipramine, an antidepressant, in poloxamer 407-induced hyperlipidaemic model rats

“…Clomipramine is a potent and selective serotonin reuptake inhibitor of the tertiary amines from the tricyclic antidepressant family [1] . It has been used for the treatment of anxiety, fear, phobias, severe depression, and obsessive–compulsive behaviour [2,3] . However, severe side effects make clomipramine medication extremely difficult [4] .…”

Pharmacokinetics of clomipramine and desmethylclomipramine after single‐dose intravenous and oral administrations in cats

“…Desmethylclomipramine (DCMP), an active hepatic metabolite, displays mostly noradrenergic activity and has been identified as responsible for the majority of the side‐effects in humans (Benfield et al. , 1980; Gex‐Fabry et al. , 2000).…”

“…, 2000). Clomipramine has been used for the treatment of anxiety, fear, phobias, severe depression and obsessive–compulsive behaviors in human patients (McTavish & Benfield, 1990; Gex‐Fabry et al. , 2000) and also to treat separation anxiety, compulsive behaviors and dominance‐related aggression in dogs (Podberscek et al.…”

“…A large 10‐ to 15‐fold interindividual variability in plasma concentrations of both clomipramine and DCMP, especially after oral administration, has been attributed to environmental and genetic factors (deCuyper et al. , 1981; Gex‐Fabry et al. , 2000).…”

“…, 1982; Noguchi et al. , 1993; DUAG – Danish University Antidepressant Group, 1999; Gex‐Fabry et al. , 2000).…”