A new predictor of toxicity following acetaminophen overdose based on pretreatment exposure

Despite extensive clinical experience, no dose-response curve exists for acetaminophen toxicity in man. The absence of accurate toxicodynamics has hampered efforts to optimize patient therapy and to identify risk modifiers following overdose. We set out to parameterize both the degree and duration of pretreatment exposure into a single, continuous measure of exposure, which will serve as the x-axis of an eventual dose-response curve.

The model was constructed from pharmacokinetic first principles, using as inputs the vertical distance above the Rumack-Matthew nomogram line (expressed as the equivalent serum acetaminophen concentration 4 h after ingestion) and the delay to antidote therapy (tNAC). A no-effect dose ([APAP]threshold) and lag time (ti) were assumed.

The area under the serum acetaminophen concentration vs. time curve bounded by [APAP]threshold, ti and tNAC represents our proposed time-weighted measure of exposure. We demonstrate that this non-negative area estimates the cellular burden of toxic adducts formed following overdose. This measure is also easily calculated at patient presentation using clinical data and allows for both declining serum acetaminophen concentrations and variable delays to antidote therapy.

We describe a new, pharmacokinetically based measure of exposure following acute acetaminophen overdose treated with N-acetylcysteine. Using this measure should enhance the analysis of nonexperimental clinical data and permit more accurate characterization of acetaminophen toxicodynamics. Ultimately, this approach may facilitate progress on many of the long-standing controversies regarding acetaminophen toxicity in man.