Physiologically based pharmacokinetic model (PBPK) for the halofantrine cardiac effect prediction – proof of concept study towards the system for the antimalarial drugs cardiac safety assessment.
Sebastian Polak 1,2, Barbara Wiśniowska 2
1 Simcyp Ltd. (part of Certara), 2 Jagiellonian University Medical College
Objectives: Antimalarial drugs help to cure the disease yet carry serious safety problems at least some of them are connected with cardiac arrhythmias, possibly fatal, in both adults and children. The aim of the study was to establish a model based cardiac safety assessment algorithm. Halofantrine, effective yet potentially cardiotoxic drugs, was chosen as an example.
Methods: Clinical data describing halofantrine (HAL) and its active metabolite N-desbutylhalofantrine (DB-HAL) plasma concentration change in time after single oral dose of 500 mg was derived from the Charbit et al. article [1]. They were used as an input for the simple empirical two-compartmental model to simulate individual concentrations for 12 virtual individuals to mimic the clinical trial. After correction by the protein binding (fu=0.004 for both moieties), the simulated individual plasma exposure was directly used as an input (concentration in the Hill equation). Information about the concentration dependent main ion currents inhibition triggered by the two entities, in a form of IC50 (micromoles) values were derived from the literature (HAL – IKr, ICa, INa; DB-HAL - IKr) or predicted with use of QSAR models (DB-HAL – ICa, INa) [2,3,4]. The IC50 values for HAL/DB-HAL for IKr, ICa, and INa currents were: 0.0216/0.0717, 1.9/6.55, 331.2/6.71 respectively. The Cardiac Safety Simulator v2.1 was used to simulate the drug-triggered ECG modification [5]. The predicted results expressed as the QT (corrected with the use of Fridericia correction formula) change relative to baseline were compared against the observed values of the same character.
Results: Comparison between observed and predicted QTc values at time 0, 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 48, 72, 168 hours after dosing was performed. The observed/predicted values, expressed as described above (% of change against baseline) for the times points listed is as follows: 0.0/0.0, -0.8/0.7, 0.1/1.4, 0.5/1.3, 1.6/1.5, 1.6/1.6, 1.0/2.0, 1.9/1.6, 2.2/2.1, 2.6/2.4, 1.2/1.3, 0.1/0.9, 0.5/1.4, -1.0 /0.6.
Conclusions: The middle-out approach (in vitro currents inhibition data combined with clinical exposure information) was applied to predict cardiac effect of the halofantrine and its active metabolite. The results prove that mechanistic modelling and simulation can be utilized for the safety assessment. For the tested concentrations halofantrine did not prolong the QT above 5% as compared against the baseline yet the prolongation effect was concentration-dependent.
References:
[1] Charbit B. et al. Pharmacokinetic and pharmacodynamic interaction between grapefruit juice and halofantrine. Clin Pharmacol Ther. 2002 Nov;72(5):514-23.
[2] Kramer J. et al. MICE models: superior to the HERG model in predicting Torsade de Pointes. Sci Rep. 2013;3:2100. [3] Mbai M. et al. The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels. Cardiovasc Res. 2002 Sep;55(4):799-805. [4] Wisniowska B. et al. Enhanced QSAR models for drug-triggered inhibition of the main cardiac ion currents. Journal of Applied Toxicology, 2015; 35(9): 1030–1039. [5] https://www.certara.com/software/pbpk-modeling-and-simulation/cardiac-safety-simulator/
