Risk assessment of accidental nortriptyline poisoning: The importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator

It is not possible to make a prospective clinical study that reveals the importance of the nortriptyline metabolising cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C19, CYP2D6, and CYP3A4) in relation to attaining potential toxic nortriptyline concentrations with a possibly fatal outcome. Therefore to study this we have applied the population based pharmacokinetic simulator Simcyp®. The objective was to estimate how important CYP2C19 and CYP2D6 phenotype status, hepatic activity of CYP3A4, body weight, CYP2D6 phenotype dose adjustment, and drug-drug interactions are with regard to accidental poisoning in a virtual population receiving a daily dose of 100mg nortriptyline. Accidental poisoning is here defined as intake of a normal dose which because of slow metabolism may lead to potentially toxic concentrations. The input parameters values for Simcyp® were based on average literature in vitro and in vivo data. The Simcyp® simulations of nortriptyline pharmacokinetics reflected reported clinical concentration-time profiles, therapeutic drug monitoring data, and the consequence of CYP2D6 poor metaboliser (PM) and ultrarapid metaboliser status. Of the investigated factors, the simulations indicate that having CYP2D6 PM status is a major risk factor for attaining high concentrations and thereby possibly becoming poisoned by nortriptyline. Of the CYP2D6 PM subjects 16% would attain plasma concentrations exceeding the toxic limit. Individuals with the combination of CYP2D6 PM status and 10% of the average liver CYP3A4 expression had a 90% risk of becoming poisoned. The results point towards the combination of low CYP3A4 activity and CYP2D6 PM status of major importance for attaining possibly toxic nortriptyline concentrations. In a forensic toxicological context, the results indicate that both the activity of CYP3A4, information on possible drug-drug interactions, and the genotype of CYP2D6 are needed in order to elucidate whether an individual might have been accidentally poisoned because of slow metabolism. In a clinical context, the simulations suggest that precise individual dose adjustment of nortriptyline requires information regarding the activity of both CYP3A4 and CYP2D6. This underlines the value of therapeutic drug monitoring for nortriptyline. Population based pharmacokinetic simulations are considered useful tools for risk assessment in clinical and forensic toxicology.

Jakob Jornil, Klaus Gjervig Jensen, Frank Larsen, Kristian Linnet
October 9, 2011
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