Background: This research project shows how a model from a prior population analysis can be used along with clinical trial simulations to give a clinical rationale for a chosen dosing regimen. Here dosing of N-acetyl cysteine (NAC) after paracetamol overdose is investigated using this methodology. NAC binds covalently to the toxic metabolite of paracetamol, n-acetyl-p-benzoquinone imine (NAPQI), preventing liver damage. The conventional dosing regimen of NAC is effective but incurs an initial delay of at least five to six hours post-overdose while a plasma paracetamol concentration is obtained; it then involves a complex three phase infusion process. The first infusion uses a high dose rate of NAC which often leads to adverse reactions. We present a new dosing regimen that should be as effective as the conventional regimen but does not have an initial delay, reduces the initial high infusion rate and simplifies the infusion regimen.
Aim: To develop a dosing regimen for NAC that can be administered immediately upon presentation of paracetamol overdose that uses a low dose rate infusion.
Methods: In this study we used clinical trial simulation to explore the concentration-time profiles of different NAC dosing regimens including the conventional regimen. We used a published population pharmacokinetic model of NAC  and in MATLAB simulated 1000 virtual patients which we dosed in a cross-over design. We assumed that the AUC of NAC equates to the effectiveness of the regimen while the Cmax drives the risk of adverse effects. A hypothetical scenario was considered where the patient arrives 2 hours post-overdose and there is a 4 hour delay before NAC treatment is initiated; this is the best case scenario. The proposed infusions started immediately on presentation of the patient. The dose was indentified to give an AUC that was the same or higher than the conventional regimen on 90% of occasions while minimising the Cmax.
Results: For the hypothetical scenario the first infusion of the conventional NAC regimen was replaced by an infusion that is 73% of the infusion rate of the conventional regimen with an infusion duration of 5 times longer. This leads to a total dose that is 14% less but attains the same AUC while having a greatly reduced Cmax.
Conclusions: Our simulations suggest that immediate low dose rate infusions of NAC may be able to replace the complex conventional regimen. The proposed regimen needs to be assessed prospectively.
- Brown M et al. Eur J Clin Pharmacol 2004;60:717-23.