Utilising prior literature population models to inform clinical practice - a dosing regimen for immediate N-acetyl cysteine treatment of paracetamol overdose
CV Coulter(1), F Shen(1), GK Isbister (2), SB Duffull(1)
(1)School of Pharmacy, University of Otago, Dunedin; (2) Department of Clinical Toxicology, Calvary Mater Hospital, Newcastle, Australia/Discipline of Clinical Pharmacology, University of Newcastle, Newcastle, Australia
Objectives: This research shows how a model from a prior population analysis can be used with clinical trial simulations to give a clinical rationale for a chosen dosing regimen. Here dosing of N-acetyl cysteine (NAC) after paracetamol overdose was investigated using this methodology. NAC acts to replenish glutathione which 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. The first infusion uses a high dose rate of NAC which can lead to adverse reactions. The aim of this study was to develop a dosing regimen for NAC that can be administered immediately upon presentation post- paracetamol overdose that uses a low dose rate infusion. This methodology gave a new dosing regimen that should be as effective as the conventional regimen but is without the initial delay and reduces the initial high infusion rate.
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 infusion started immediately on presentation to hospital. The dose rate was selected to give an AUC that was the same or higher than the conventional regimen on 90% of occasions while reducing the Cmax.
Results: For the hypothetical scenario the conventional NAC regimen was replaced by an infusion of 200 mg/kg over 9 hours then 100 mg/kg over 16 hours. This regimen has a longer infusion duration and a greatly reduced Cmax, compared to the conventional regimen.
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.