The use of a population approach in paraquat toxicokinetic/dynamic study

Background: Paraquat poisoning is a common and serious medical problem in many parts of Asia and the Pacific. The mortality rate of this herbicide is extremely high as there is no specific and effective treatment.
Aim: We analysed 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 nonlinear mixed effects approach was used to perform toxicokinetics/toxicodynamic population analysis in a subset of 78 patients.
Results: A two-compartment model best fitted the toxicokinetic data. The estimates of toxicokinetic parameters for the apparent clearance (CLPQ/F), the apparent volume of distribution (Vd/F) and elimination half-life (t1/2 β) were 1.17 L/h, 2.4 L/kg 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 over 24 to 48 h, and afterward the clearance was constant over time. The model estimated that a peak paraquat concentration of only 429 µg/L caused 50% of maximum renal toxicity. Immunosuppressive therapy was associated with only slightly better renal function (8% better than placebo).
Conclusion: The models may be useful as a prognostic tool to indicate patient status on admission. They can be used to predict the time-course changes of kidney function following paraquat intoxication. The low clearance and long half-life suggest further studies of extracorporeal elimination techniques would be worthwhile.