In silico prediction of the drug overdose consequences at the heart electrophysiology level

The aim of the study was to simulate the possible clinical situation of the drug overdose and to assess its electrophysiological consequences, and thus to move the M&S approach to the patient's bedside level. Cardiological consequences of citalopram overdose were simulated with use of the ToxComp system. Physiology of the 36-yo woman, 33 hours post suicidal ingestion, with high serum citalopram (477 ng/mL) and its metabolite desmethylcitalopram (123.2 ng/mL) concentration was simulated. Ionic current inhibition data were either taken from the literature or predicted with use of the extended QSAR models. Total ionic currents inhibition was simulated as the sum of inhibitions. Plasma ions concentrations and heart rate rhythm were taken from the clinical report (Tarabar 2008). QTc [ms] value with Fridericia correction was the endpoint. Four scenarios were tested assuming that either I
_Kr
current only or I
_Kr
+I
_Ks
currents are affected with various heart rates. The comparison of the observed vs. simulated QTcF values for four tested scenarios was as follows: (1) I
_Kr
/102 bpm - 524/469; (2) I
_Kr
/150 bpm - 515/511; (3) I
_Kr
+I
_Ks
/102 bpm - 524/487; (4) I
_Kr
+I
_Ks
/150 bpm - 515/524. ToxComp system predicted the electrophysiological consequences of citalopram overdose. Results indirectly suggest the role of the drug triggered multiple currents inhibition instead of dealing with hERG channel only.