Anderson JM (1,2,3) Petersson K (3) Friberg L (3) Worek F (4), Thiermann H (4), Buckley NA (1,2).
1. South Asian Clinical Toxicology Research Collaboration, Sri Lanka 2. University of New South Wales; 3. Department of Pharmaceutical Biosciences, Uppsala University; 4. Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Objectives: : Death from chlorpyrifos (CPF) poisoning, a common organophosphorus (OP) pesticide is an increasingly worrying problem in Sri Lanka. However, inaccurate information regarding dose amount and time are common in the data collected and make appreciation of lethal dose difficult. It would be useful to characterise the PKPD relationships involved to better understand the time course of poisoning and potential hazards. The aim of this project is to extend upon a previous PK model to incorporate PD aspects of organophosphate acute poisoning.
Methods: A PK model for CPF and its metabolites was developed using NONMEM 7.2. The model was derived from sparse acute poisoning data from patients (n = 75; 7 Female, age 15-65, 2-8 samples per subject). The reported volumes ingested ranged from 10 to 350 ml. CPF, chlorpyrifos oxon (CPO), RBC-AChE, BChE, and urinary metabolites were measured at each time point. Â
Results:A 2-compartment model for the parent compound with first order absorption kinetics and a one compartment disposition for the metabolite chlorpyrifos oxon best described the data. Dose uncertainty was accounted for by allowing each individual’s dose to deviate from the median dose volume of 50mls using the reported volume intake as a covariate on the bioavailability parameter. For the parent Ka was estimated and fixed to 1.64 (Hr), Cl was 0.9 (L/Hr) SE 0.109, and Vd was7.39 (L) SE 1.3, with a residual error of 37%. The estimated dose range was on average 30mls less than reported. The CPO data collected was too highly variable for validation however Cl and Vd are both large and correlated with CPF. A turnover model was developed to describe the CPF – AChE and BChE(enzymes, biomarkers of toxicity) relationship, with an proportional Emax model on the elimination of the enzyme. Â
Conclusion: The developed PK model could well characterise the observed concentrations of 0.1 – 18.32 nM. CPO data was too variable for validation completion. Survival PD data is currently being incorporated into the model including cholinesterase inhibition, an important biomarker. We hope this extended model will help us to better understand acute chlorpyrifos poisoning toxicology and the relationship between dose and PD outcomes.Â
Reference: PAGE 21 (2012) Abstr 2555 [www.page-meeting.org/?abstract=2555]
Poster: Other Drug/Disease Modelling