PK modelling of organophosphorus poisoning in humans
Anderson JM (1,2,3) Petersson KJ (3) Friberg LE (3) Worek F (4), Thiermann H (4), Buckley NA (1,2).
South Asian Clinical Toxicology Research Collaboration, Sri Lanka 2. University of New South Wales; 3. Deparment of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden 4. Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany.
Objectives: Organophosphorus (OP) pesticide poisoning is an important problem in South Asia, acute poisoning from OP’s in Sri Lanka resulted in 853 deaths in 2007 with the incidence increasing1. Characterization of the dose-concentration-response relationship would be useful to understand the time-course of acute poisoning. However, accurate information on dose amount and time of ingestion is generally lacking. We therefore aimed to develop PK and PKPD models of OP’s in acute poisoning.
Methods: A PK model for one OP, chlorpyrifos (CPF) and its metabolties was developed using NONMEM VI. The model was derived from acute poisoning data from patients (n = 72; 7 Female, age 15-65 years, 2-8 samples per subject). The reported volumes ingested ranged from 10 to 350 ml. CPF, chlorpyrifos oxon (CPO).
Results: A 2-compartment model for CPF with first order absorption kinetics best described the data. Dose uncertainty was accounted for by allowing each individual’s dose to deviate from the median dose of 50mls using the reported volume intake as a covariate on the relative bioavailability parameter. For CHL Ka was fixed to 0.48 (Hr), Cl was 0.86 (L/hr) RSE 11%, Vc 1.64 (L) RSE36%, Vp 37.34 (L) RSE 16.22% and Q was 1.9 RSE 17.52%. A proportional residual error was estimated to 36%. The estimated dose range was smaller than reported.
Conclusions: The PK model developed characterised the observed concentrations of 0.1 – 19 nM well with reasonable estimates of the dose range. Future investigations are planned to incorporate PD data including cholinesterase inhibition, an important biomarker, and survival data. We hope this model will help us to better understand acute and chronic chlorpyrifos poisoning toxicology, the relationship between dose and PD outcomes and potential treatment options.
References:
[1]. Statistics AH, AH Statistics, Editor 2007, Medical Statistics Unit, Sri Lanka p38.
Abbreviations: AChE, acetylcholinesterase (EC 3.1.1.7); BChE, butyrylcholinesterase (EC 3.1.1.8); CPF, chlorpyrifos; CPO, chlorpyrifos oxon; RBC, red blood cells; Vp, peripheral compartment volume.