Nonlinear mixed effects modelling approach in investigating amitriptyline pharmacokinetics
Jovanović M (1), Vučićević K (1), Golubović B (1), Ćulafić M (1), Timotijević I (2), Pokrajac M (1), Miljković B (1)
(1) Department of Pharmacokinetics and Clinical Pharmacy, University of Belgrade - Faculty of Pharmacy, Belgrade, Serbia; (2) Institute of Mental Health, University of Belgrade - School of Medicine, Belgrade, Serbia
Objectives: The aim of the study was to investigate pharmacokinetic characteristics of amitriptyline (AMT) and influence of different variability factors in patients with depression.
Methods: A total of 280 AMT concentrations were obtained from depressive patients after administration of single dose. An average dose of AMT was 91.07 ± 31.34 mg. Pharmacokinetic analysis was performed by nonlinear mixed effects modelling using NONMEM® software (version 7 level 2) and Perl speaks NONMEM® (version 3.5.3). Parameters estimation was performed by FOCE with interaction. Influence of AMT dose, demographic characteristic and co-therapy on AMT CL/F was investigated.
Results: Structural model was developed as a one-compartment model with first-order absorption and elimination implemented in ADVAN2/TRANS2 subroutine. The interindividual variability was evaluated by an exponential model while residual variability was best described by proportional model. The estimated CL/F was 70.4 (66.36 - 74.44) l/h, V/F was 1300 (1216 - 1384) l and ka was 0.633 (0.497 - 0.769) h-1, for a typical patient. Among tested covariates, only influence of weight on CL/F was significant (p<0.01). Inclusion of covariate into the base model decreased interindividual coefficient of variability for CL/F, and in the final model it was 8%. There were no significant impact of gender, AMT dose and co-therapy with lithium and fluvoxamine on AMT elimination. Residual variability in the final model was 0.29 (0.266 - 0.315). Acceptable model performances were confirmed by adequate diagnostic plots and internal validation.
Conclusions: The final population AMT model describes and quantifies influence of weight on AMT elimination in patients with depression. The results can be used for estimation of CL/F and individualization of dosing regimen.
References:
[1] Vezmar S, Miljkovic B, Vucicevic K, Timotijevic I, Prostran M, Todorovic Z, Pokrajac M. Pharmacokinetics and efficacy of fluvoxamine and amitriptyline in depression. J Pharmacol Sci. 2009;110(1):98-104.
