A kinetic-pharmacodynamic model for clinical trial simulation of antidepressant action: Application to clomipramine–lithium interaction

• Published in: Contemporary clinical trials Vol. 28; no. 3; pp. 276 - 287
• Main Authors: Gruwez, Bérangère, Poirier, Marie-France, Dauphin, Alain, Olié, Jean-Pierre, Tod, Michel
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.05.2007; Elsevier
• Subjects: Antidepressant; Antidepressive Agents - pharmacology; Antidepressive Agents - therapeutic use; Biological and medical sciences; Cardiovascular; Clinical trial simulation; Clinical trial. Drug monitoring; Clomipramine; Clomipramine - pharmacology; Clomipramine - therapeutic use; Data Interpretation, Statistical; Depressive Disorder - drug therapy; Double-Blind Method; Drug Therapy, Combination; Female; General pharmacology; Hematology, Oncology and Palliative Medicine; Humans; Lithium; Lithium Carbonate - pharmacology; Lithium Carbonate - therapeutic use; Male; Medical sciences; Middle Aged; Models, Biological; Pharmacokinetic–pharmacodynamic model; Pharmacology. Drug treatments; Randomized Controlled Trials as Topic - methods; Antidepressant; Clinical trial simulation; Lithium; Clomipramine; Pharmacokinetic–pharmacodynamic model; Pharmacokinetic pharmacodynamic relationship; Psychotropic; Reuptake inhibitor; Pharmacokinetic-pharmacodynamic model; Antidepressant agent; Clinical trial; Drug interaction; Human; Drug combination; Pharmacodynamics; Serotonin; Catecholamine; Tricyclic compound; Biological activity; Treatment; Simulation; Nootropic agent; Neurotransmitter; Norepinephrine; Models; Pharmacokinetics; Dibenzazepine derivatives
• ISSN: 1551-7144; 1559-2030
• DOI: 10.1016/j.cct.2006.09.001

Abstract A generic kinetic-pharmacodynamic (K-PD) model to describe the response to treatment assessed by a clinical score for depressed patients treated by antidepressants alone or combined with a drug that shortens the lag-time before effect was developed. The aims of this study were: (1) to verify model's ability to characterize clinical data, (2) to evaluate several statistics to summarize the clinical effect, (3) to compare the analysis based on these statistics to the conventional intent-to-treat analysis and (4) to determine the optimal dates of clinical assessment. The population K-PD model was fitted to the individual data from a randomized clinical trial assessing the efficacies of clomipramine and placebo or clomipramine and lithium to treat major depression in 141 patients. The K-PD model was able to fit the individual data even in the case of oscillating score profiles. The interindividual coefficient of variation of the model parameters ranged from 33 to 161%. The statistical analysis based on the secondary parameters yielded conclusions comparable to those of the conventional intent-to-treat analysis. The population model was then used for a clinical trial simulation. According to the simulation, the most sensitive summary statistics for detecting a difference between lithium and placebo were the fractional reduction of depression and the proportion of responders. The optimal dates to assess these parameters were day 9 and 11 respectively. The K-PD model might serve as a tool for clinical trial planning in the field of research on antidepressants and their facilitators.