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Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach.

Abstract：

AIMS:Paraquat poisoning is a medical problem in many parts of Asia and the Pacific. The mortality rate is extremely high as there is no effective treatment. We analyzed data collected during an ongoing cohort study on self-poisoning and from a randomized controlled trial assessing the efficacy of immunosuppressive therapy in hospitalized paraquat-intoxicated patients. The aim of this analysis was to characterize the toxicokinetics and toxicodynamics of paraquat in this population. METHODS:A non-linear mixed effects approach was used to perform a toxicokinetic/toxicodynamic population analysis in a cohort of 78 patients. RESULTS:The paraquat plasma concentrations were best fitted by a two compartment toxicokinetic structural model with first order absorption and first order elimination. Changes in renal function were used for the assessment of paraquat toxicodynamics. The estimates of toxicokinetic parameters for the apparent clearance, the apparent volume of distribution and elimination half-life were 1.17 l h(-1) , 2.4 l kg(-1) and 87 h, respectively. Renal function, namely creatinine clearance, was the most significant covariate to explain between patient variability in paraquat clearance.This model suggested that a reduction in paraquat clearance occurred within 24 to 48 h after poison ingestion, and afterwards the clearance was constant over time. The model estimated that a paraquat concentration of 429 μg l(-1) caused 50% of maximum renal toxicity. The immunosuppressive therapy tested during this study was associated with only 8% improvement of renal function. CONCLUSION:The developed models may be useful as prognostic tools to predict patient outcome based on patient characteristics on admission and to assess drug effectiveness during antidote drug development.

journal_name

Br J Clin Pharmacol

journal_title

British journal of clinical pharmacology

authors

Wunnapuk K,Mohammed F,Gawarammana I,Liu X,Verbeeck RK,Buckley NA,Roberts MS,Musuamba FT

doi

10.1111/bcp.12389

subject

Has Abstract

pub_date

2014-10-01 00:00:00

pages

855-66

issue

eissn

0306-5251

issn

1365-2125

journal_volume

pub_type

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Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach.