Pharmacokinetic/pharmacodynamic modeling of cardiac toxicity in human acute overdoses: utility and limitations.
BACKGROUND
Hypotension, cardiac failure, QT interval prolongation, dysrhythmias, and conduction disturbances are common complications of overdoses with cardiotoxicants. Pharmacokinetic/pharmacodynamic (PK/PD) relationships are useful to assess diagnosis, prognosis, and treatment efficacy in acute poisonings.


OBJECTIVE
To review the utility and limits of PK/PD studies of cardiac toxicity.


METHODS
Discussion of various models, mainly those obtained in digitalis, cyanide, venlafaxine and citalopram poisonings.


CONCLUSIONS
A sigmoidal E(max) model appears adequate to represent the PK/PD relationships in cardiotoxic poisonings. PK/PD correlations investigate the discrepancies between the time course of the effect magnitude and its evolving concentrations. They may help in understanding the mechanisms of occurrence as well as disappearance of a cardiotoxic effect. When data are sparse, population-based PK/PD modeling using computer-intensive algorithms is helpful to estimate population mean values of PK parameters as well as their individual variability. Further PK/PD studies are needed in medical toxicology to allow understanding of the meaning of blood toxicant concentration in acute poisonings and thus improve management.
Mégarbane
Bruno
B
Hôpital Lariboisière, Réanimation Médicale et Toxicologique, 2 rue Ambroise Paré, 75010, Paris, France. bruno-megarbane@wanadoo.fr
Aslani
Arsia Amir
AA
Deye
Nicolas
N
Baud
Frédéric J
FJ
D000208:Acute Disease; D000818:Animals; D062787:Drug Overdose; D006331:Heart Diseases / Q000139:chemically induced*; D006801:Humans; D008954:Models, Biological; D010599:Pharmacokinetics