Population pharmacokinetic–pharmacodynamic modelling to describe the effects of paracetamol and N‐acetylcysteine on the international normalized ratio
Open accessAbstract
Summary: Paracetamol is one of the most common pharmaceutical agents taken in self‐poisonings, and can increase the prothrombin time (PT) through liver injury, and in overdose without hepatic injury by reducing functional factor VII. PT is a measure of hepatic injury used to predict and monitor hepatotoxicity, reported as the international normalized ratio (INR). The antidote for paracetamol poisoning, N‐acetylcysteine (NAC), has been reported to have an effect on the PT. This analysis included patients from a retrospective case series, a prospective inception cohort of paracetamol and psychotropic (control) overdoses, and a cross‐over clinical trial. A population pharmacokinetic–pharmacodynamic model describing the pharmacodynamic effects of paracetamol and NAC on the INR was developed in Phoenix NLME. The dataset included 172 patients; the median age was 22 years (range 13–71 years). A one‐compartment model with first‐order input and linear disposition best described paracetamol pharmacokinetics. The population mean estimate of the concentration that induced a response halfway between the baseline and maximal pharmacological effect of paracetamol was 1302 μ mol/L (242), the maximum effect of paracetamol was 0.534 (202; from baseline) and the maximum effect of NAC was 0.325 (9.03; from baseline). Both paracetamol and NAC contributed a pharmacological effect to the elevation of INR. The estimated paracetamol concentration that induced a response halfway between the baseline and maximal pharmacological effect was within the range of plasma paracetamol values studied, fivefold greater than the maximum therapeutic concentration, suggesting that an elevated INR would not be expected within the therapeutic range. Simulated 24 and 48 g paracetamol overdoses with NAC administration produced INR values (50th percentile) that reached the upper limit of, or exceeded, the reference range.
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Paracetamol overdose and acetylcysteine can both directly cause a mildly prolonged INR and thus the test is only useful in established hepatotoxicity.
“However, paracetamol overdose and acetylcysteine can both directly cause a mildly prolonged INR and thus the test is only useful in established hepatotoxicity [91].”
From Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease (2023) · cites this paper as [91]
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- Authors
- Owens, K. H., Medlicott, N. J., Zacharias, M., Whyte, I. M., Buckley, N. A., & Reith, D. M.
- Affiliations
- University of Otago (NZ)
- Dunedin Public Hospital (NZ)
- Calvary Mater Newcastle Hospital (AU)
- The University of Sydney (AU)
- Corresponding author
- Owens, Katie H
- Venue
- Clinical and Experimental Pharmacology and Physiology
- Publisher
- Wiley
- Published
- 2014-12-22
- Volume
- 42
- Issue
- 1
- Pages
- 102-108
- ISSN
- 0305-1870 (ISSN-L)
- 1440-1681
- OpenAlex
- W1976808864
- Cited by
- 11
- References
- 21
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 1 · 2015: 1
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical and Experimental Pharmacology and Physiology (publishedVersion)
- PubMed (publishedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Emergency Medicine › Poisoning and overdose treatments
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- paracetamol, N-acetylcysteine, international normalized ratio, prothrombin time, acetaminophen overdose, acetaminophen toxicity, antidotes, hepatotoxicity, factor VII, pharmacokinetic-pharmacodynamic modeling, self-poisoning
- MeSH terms
- Acetaminophen, Acetylcysteine, Adolescent, Adult, Aged, Double-Blind Method, Female, Humans, Male, Middle Aged, Models, Biological, Prospective Studies, Retrospective Studies, Cohort Studies, Cross-Over Studies, Analgesics, Non-Narcotic, International Normalized Ratio, Young Adult
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