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Prediction of paraquat exposure and toxicity in clinically ill poisoned patients: a model based approach
Author(s) -
Wunnapuk Klintean,
Mohammed Fahim,
Gawarammana Indika,
Liu Xin,
Verbeeck Roger K.,
Buckley Nicholas A.,
Roberts Michael S.,
Musuamba Flora T.
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12389
Subject(s) - toxicodynamics , paraquat , toxicokinetics , renal function , population , volume of distribution , medicine , cohort , pharmacology , toxicity , toxicology , chemistry , pharmacokinetics , biology , biochemistry , environmental health
Aims Paraquat poisoning is a medical problem in many parts of A sia and the P acific. 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.