Sean Oosterholt [1], Yaiza O Ruiz [1], Magdalena Tchorek-Bentall 2], Daniel Marks [2], Oscar Della Pasqua [1]
[1] Clinical Pharmacology & Therapeutics Group, University College London, London, UK [2] University College London Hospitals NHS Foundation Trust
Introduction: Paracetamol is the commonest drug taken in overdose in the United Kingdom, accounting for 48% of all poisoning admissions to hospital and an estimated 100–200 deaths per year. The recommended dosing regimen for treating acetaminophen (APAP) overdose consists of an intravenous dose of N-acetylcysteine (NAC) 150mg/kg over 60 minutes, then 50mg/kg over 4 hours and finally 100mg/kg over 16 hours. Empirical evidence suggests that this protocol is both effective and safe, but increased incidence of cases in which patients taking massive overdoses (> 30 g APAP) have had poor outcome seems to highlight the need of a stoichiometric basis for the current regimen. We critically evaluate the current nomogram and explore the correlation between APAP overdose and NAC regimens using modelling and simulation.
Methods: A population pharmacokinetic modelling approach was used to characterise the disposition of APAP and NAC. Published literature was used for the APAP model, NAC model building was based on digitized profiles of three studies published in literature. Model parameters were subsequently used to simulate both moieties according to the available clinical information (overdose time, overdose amount and NAC treatment) and explore the implications of variable exposure to NAC on treatment outcome in a cohort of 28 patients, who were admitted and treated for paracetamol overdose at a tertiary London hospital. Ethics approval was obtained for the review and analysis of the data. NONMEM version 7.3 and PsN version 4.6.0 were used for the modelling and simulation, R version 3.5.1 (2018-07-02) was used for statistical and graphical summaries.
Results: A review of the clinical records showed that eight (28.6%) patients reported opioid co-ingestion, and eleven (39.3%) of overdoses were staggered. The reported ingested dose was 12g (IQR: 8-21g, maximum 56g). The median plasma paracetamol concentration at presentation was 50.9mg/L (18.55-101.025mg/L, maximum 305.2mg/L). All patients received N-acetylcysteine, with a median dose of 22.9g (IQR: 19.8-30.7g), whereas six (21.4%) patients had additional NAC infusions beyond 21-hours of treatment. Despite prompt intervention, twelve patients (42.9%) developed an ALT rise above the upper limit of normal, with 6 (21.4%) above 1000IU/L, and 5 (17.9%) of patients had an INR rise to >1.3. Simulated APAP and NAC profiles shed further light on the limitations of the nomogram for APAP intoxication lack of a stoichiometric basis for the current NAC regimen. Furthermore, the slope of the correlation between APAP and NAC exposure was found to be -0.02 and 0.09 for Cmax and AUC respectively.
Conclusion: NAC remains an important measure for the prevention of severe hepatic damage following APAP overdose. Current NAC therapy recommendations have been effective, but evolving insight from pharmacokinetic modelling and simulation demonstrates that its regimen can be optimised. Most importantly, simulations make clear that a revised nomogram is needed to ensure appropriate clinical management of acute overdose.
Reference: PAGE 28 (2019) Abstr 9075 [www.page-meeting.org/?abstract=9075]
Poster: Drug/Disease Modelling - Other Topics