Just say no to postmortem drug dose calculations

Abstract

For years, a number of professional groups have warned forensic and clinical toxicologists against calculating an administered dose of a drug based on postmortem blood drug concentrations. But to date, there has been limited information as to how unreliable these dose calculations may actually be. Using amitriptyline as a model drug, this study used empirically determined pharmacokinetic variables for amitriptyline from clinical studies coupled with clinical overdoses (where the individual survived), and death case studies (ascribed to amitriptyline toxicity) in which the dose of amitriptyline was known. Using these data, standard pharmacokinetic equations, and general error propagation, it was possible to estimate the accuracy of calculated doses of amitriptyline, compared with the doses that were consumed. As was expected in postmortem cases, depending on the pharmacokinetic equation used, the accuracy (mean +128% to +2347%) and precision (SD ± 383% to 3698%) were too large to allow reliable estimations of the dose of amitriptyline consumed prior to death based on postmortem blood drug concentrations. This work again reinforces that dose calculations from postmortem blood drug concentrations are unreliable.

Difficulties associated with the interpretation of postmortem toxicology

“…After death, a series of changes ensue that collectively influence the distribution of compounds in the body over time. As such, a PM drug concentration may not be an accurate representation of the drug concentration that was present during life [ 1 ]. For this reason, dose estimations should only be made with an acknowledgement of the limitations of interpreting PM results [ 2 , 3 ].…”

Monte Carlo optimization method based QSAR modeling of postmortem redistribution of structurally diverse drugs

“…[8][9][10][11][12] The competing diffusion processes from the drug reservoirs mentioned above, followed by cellular membrane disruption and putrefaction, and the specific pharmacokinetic properties of certain drugs, can give rise to drug concentration alterations between sampling intervals and sites. 13,14 Drug biotransformation through metabolising enzymes, such as cytochrome P450 (CYP) monooxygenases and/or uridine diphosphateglucuronosyltransferases (UGT), may likewise be triggered during the early post-mortem period steps. 15,16 For this reason, the interpretation of analytical results in forensic toxicology may be complicated by drug PMR.…”