Simulation of pharmacokinetics of amitriptyline and nortriptyline and their common effect on human cardiac electrophysiology in healthy population
Zofia Tylutki (1), Sebastian Polak (1,2)
(1) Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland, (2) Simcyp (a Certara Company) Limited, Sheffield, UK
Objectives: In assessing drug triggered cardiac effect the parent drug and its metabolites’ exposure in cardiac tissue seems to be of particular interest, although drug level in plasma is the most commonly used as the effective concentration surrogate. The aim of the study was to simulate drug influence on the electrophysiology of human cardiomyocytes in the population, taking into account individual PBPK model-predicted drug and its metabolite concentrations both, in heart and plasma. Amitriptyline and nortriptyline were used as the model substances.
Methods: Amitriptyline time-concentrations profiles in plasma and heart tissue were simulated in a whole-physiologically-based pharmacokinetic (PBPK) model with four-compartment heart model nested in[1]. The model has been extended with the minimum-PBPK model for the metabolite[2] consisted of 4 compartments (plasma, heart, liver, and rest of the body) of physiological volumes and blood flows. 3 parameters were fitted to the clinical data, and the simulation scenario followed study methodology[3]. The models were written in R v.3.3.2. After defining the dose amount (single oral dose of 75 mg), number of individuals (8), number of females (0), and age range (20 – 28) the sex- and age- dependent physiological model parameters were randomized. Predicted individual free concentrations of amitriptyline and nortriptyline both, in plasma and heart, were combined with patient-specific parameters and in vitro ion channel inhibition to simulate pseudoECG traces in Cardiac Safety Simulator (CSS)[4], and ∆QTcB was an ultimate endpoint.
Results: After 10 iterations of the simulation the mean difference between the length of QTcB after drug administration and at baseline (∆QTcB) simulated for free plasma and free heart tissue were in the range from -3.29 ms 1 h postdose to 4.38 ms 6 h postdose.
Conclusions: Simulated ∆QTcB value did not exceed 5 ms (value of regulatory concern) in neither of the assessed time points. The simulated study was negative regarding a threshold pharmacologic effect on myocardial repolarization which was in accordance with in vivo observations[3]. The results of this study support the predictive abilities of in silico simulations as well as PBPK modeling.
References:
[1] Tylutki, Z, Polak, S. Scientific Reports, 7 (2017): 39494.
[2] Cao, Y, Jusko, W. Journal of Pharmacokinetics and Pharmacodynamics, 39 (2012): 711-723.
[3] Pickup, AJ et al. Journal of Cardiovascular Pharmacology, 4 (1982): 575-83.
[4] Glinka, A, Polak, S. Toxicology Mechanisms and Methods, 25 (2015): 279-286.
