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Paroxetine: population pharmacokinetic analysis in late-life depression using sparse concentration sampling
Yan Feng1, Bruce G Pollock, Robert E Ferrell
1Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, PA 15261, USA, and Rotman Research Institute, Baycrest Hospital, University of Toronto, Canada.
British Journal of Clinical Pharmacology
|May 4, 2006
Summary
This study developed a paroxetine population pharmacokinetic model in elderly depressed patients. Results show that weight, sex, and CYP2D6 genotype significantly impact paroxetine metabolism, suggesting individualized dosing for optimal treatment.
Area of Science:
- Pharmacokinetics
- Pharmacogenomics
- Geriatric Psychiatry
Background:
- Major depressive disorder is prevalent in the elderly.
- Long-term treatment with antidepressants like paroxetine requires understanding pharmacokinetic variability.
- CYP2D6 genotype is a known factor influencing drug metabolism.
Purpose of the Study:
- To develop a population pharmacokinetic (PK) model for paroxetine in elderly depressed subjects.
- To investigate the influence of covariates, including CYP2D6 genotype, on paroxetine PK during long-term treatment.
- To inform individualized dosing strategies for paroxetine in this population.
Main Methods:
- A population PK model was developed using nonlinear mixed-effects modeling (NONMEM).
- Data from elderly subjects (age ≥70) in the MTLD-2 trial with sparse paroxetine plasma concentrations were analyzed.
- CYP2D6 genotype was determined, and the effects of covariates (age, weight, sex, race, CYP2D6 genotype) on PK parameters were evaluated.
Main Results:
- A two-compartment nonlinear PK model best described paroxetine disposition.
- Weight and CYP2D6 genotype significantly affected the maximal velocity (Vm) of paroxetine elimination.
- Sex influenced the volume of distribution of the central compartment.
Conclusions:
- The developed population PK model adequately describes paroxetine pharmacokinetics in elderly depressed patients.
- CYP2D6 genotype and sex are key determinants of paroxetine elimination rates.
- Individualized paroxetine dosing based on CYP2D6 genotype may be necessary for effective and safe treatment in the elderly.
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