Klintean Wunnapuk (1,2) , Fahim Mohammed (3,4,5), Indika Gawarammana (3,4,5), Xin Liu (1), Roger K. Verbeeck (6,7), Nicholas A. Buckley (5,8,9), Michael S. Roberts (1,10), Flora T. Musuamba (6)
(1) Therapeutics Research Centre, School of Medicine, University of Queensland, Brisbane, QLD, Australia (2) Department of Forensic Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand (3) Department of Pharmacology, Faculty of Medicine, University of Ruhuna, Sri Lanka. (4) Department of Medicine, Faculty of Medicine, University of Peradeniya, Sri Lanka (5) South Asian Clinical Toxicology Research Collaboration, Faculty of Medicine, University of Peradeniya, Sri Lanka (6) Louvain Drug Research Institute, Louvain Centre for Toxicology and Applied Pharmacology, Catholic University of Louvain, Brussels, Belgium (7) Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa (8) Australian National University, Canberra, Australia (9) Professorial Medicine Unit, University of New South Wales, NSW, Australia (10) School of Pharmacy & Medical Science, University of South Australia, Adelaide, SA, Australia
Objectives: Paraquat (PQ) is a commonly used herbicide that has caused many accidental or intentional deaths. Only a few studies have been done on PQ toxicokinetics (TK) in humans (1, 2). In this study a population TK analysis was performed to estimate the typical TK parameters and interindividual variability of PQ distribution in intoxicated patients. Potential covariates were explored as well.
Methods: A TK model for PQ was developed using Phoenix NLME version 1.2. PQ plasma concentrations from 78 poisoning patients were used in the analysis. A two-compartmental TK model with first-order absorption and first-order elimination was fit to the data when choosing the basic structural model. The model was parameterized with apparent oral clearance (CLPQ/F), apparent volume of distribution of central compartment (V1/F), apparent volume of distribution of peripheral compartment (V2/F), inter-compartmental clearance (Q/F), absorption rate constant (Ka) and bioavailability factor (XF). Stepwise approach was used for TK covariate model building with forward inclusion followed by backward exclusion. The following covariates were assessed for their effects on PQ disposition: body weight (BW, kg), amount of ingestion (g) and renal function markers: serum creatinine concentration (sCr, mg/dL) and estimated creatinine clearance (eCLcr, L/h).
Results: As the ingested dose was estimated from volume of ingestion, the varying doses were imputed as covariates on the bioavailability factor and the median dose of PQ (10 g) was given as the amount administered to each patient. The typical value of Ka and V2/F were fixed to 1/h and 86 L, respectively. The typical CLPQ/F was 0.15 L/h (31%CV) and V1/F was 13.63 L (16%CV). The proportional and additive residual errors were 48% (39%) and 0.89 µg/L, respectively. The visual predictive check showed that approximately 95% of the observed data appear to fall within the 95% confidence interval indicating the accuracy of the model. Bayesian estimations of CLPQ/F and V1/F were 1.17 L/h and 0.33 L, respectively.
Conclusions: This TK model was well characterised PQ plasma concentration-time profile in patient with renal alteration. Future study are planned to incorporate PD data using renal function as an outcome.
References:
[1] Houze P, Baud FJ, Mouy R, Bismuth C, Bourdon R, Scherrmann JM. Toxicokinetics of paraquat in humans. Hum Exp Toxicol. 1990;9(1):5-12. Epub 1990/01/01. 2.Baud FJ, Houze P, Bismuth C, Scherrmann JM, Jaeger A, Keyes C. Toxicokinetics of paraquat through the heart-lung block. Six cases of acute human poisoning. J Toxicol Clin Toxicol. 1988;26(1-2):35-50. Epub 1988/01/01.
Reference: PAGE 22 (2013) Abstr 2821 [www.page-meeting.org/?abstract=2821]
Poster: Other Modelling Applications