Population pharmacokinetics of clomipramine, desmethylclomipramine, and hydroxylated metabolites in patients with depression receiving chronic treatment: model evaluation.
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.
Gex-Fabry
M
M
Department of Psychiatry, Geneva University Hospitals, Switzerland.
Haffen
E
E
Paintaud
G
G
Bizouard
P
P
Sechter
D
D
Bechtel
P R
PR
Balant
L P
LP
D000328:Adult; D000368:Aged; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002997:Clomipramine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D003198:Computer Simulation; D003863:Depression / Q000188:drug therapy / Q000378:metabolism*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D006900:Hydroxylation; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D015203:Reproducibility of Results
D000929:Antidepressive Agents, Tricyclic; C012273:desmethylclomipramine; C053390:8-hydroxyclomipramine; D002997:Clomipramine