Population Pharmacokinetic Modelling of Amitriptyline in Depression Patients
K. Vucicevic(1), B. Miljkovic(1), M. Pokrajac (1), I. Grabnar(2)
(1) Department of Pharmacokinetics, Faculty of Pharmacy, University of Belgrade, Serbia; (2) Faculty of Pharmacy, University of Ljubljana, Slovenia
Objectives: This study aimed to characterize population pharmacokinetics of amitriptyline (AMT), in order to identify possible influential covariates and to assess the linearity of AMT kinetics.
Methods: In total 428 plasma samples were obtained from 28 patients diagnosed with major depression after single AMT dose of 75mg or 150mg, and in steady-state achieved with t.i.d. doses. Population PK analysis was performed using NONMEM and Visual-NM. Data were fitted with one and two compartment models for both AMT and its active metabolite nortriptyline (NT), while FOCE INTERACTION was used for estimation. The influences of patients’ weight, age, sex, co-therapy with fluvoxamine or lithium, daily dose of AMT on PK parameters were examined.
Results: The analysis showed that kinetics of AMT followed two-compartment model with first-order absorption and lag-time. No effect of dose on pharmacokinetic parameters was observed and the individual parameters estimated from steady state data were comparable to parameters estimated from single dose data. Mean (s.e.) parameter estimates were: CL=64.6 (1.5) L/h, Vc=896 (95) L ,Vp=641 (134) L, Q=114 (21) L/h, Ka=0.73 (0.13) h-1, Tlag=0.634 (0.032) h. Interindividual variability of AMT parameters was low and was best described by exponential error model, while proportional error model the most adequately characterized residual variability in AMT concentrations. NT kinetics was formation rate limited. Simultaneous fitting of parent drug and metabolite was a further step in modeling process.
Conclusions: The NONMEM analysis showed linear kinetics of AMT with no significant effect of tested covariates on AMT PK parameters.