title: Population Pharmacokinetics of an Indian F(ab')2 Snake Antivenom in Patients with Russell's Viper (Daboia russelii) Bites.
abstract: BACKGROUND
  There is limited information on antivenom pharmacokinetics. This study aimed to investigate the pharmacokinetics of an Indian snake antivenom in humans with Russell's viper bites.
  
  
  RESULTS
  Patient data and serial blood samples were collected from patients with Russell's viper (Daboia russelii) envenoming in Sri Lanka. All patients received Indian F(ab')2 snake antivenom manufactured by VINS Bioproducts Ltd. Antivenom concentrations were measured with sandwich enzyme immunoassays. Timed antivenom concentrations were analysed using MONOLIXvs4.2. One, two and three compartment models with zero order input and first order elimination kinetics were assessed. Models were parameterized with clearance (CL), intercompartmental clearance (Q), central compartment volume (V) and peripheral compartment volume (VP). Between-subject-variability (BSV) on relative bioavailability (F) was included to account for dose variations. Covariates effects (age, sex, weight, antivenom batch, pre-antivenom concentrations) were explored by visual inspection and in model building. There were 75 patients, median age 57 years (40-70 y) and 64 (85%) were male. 411 antivenom concentration data points were analysed. A two compartment model with zero order input, linear elimination kinetics and a combined error model best described the data. Inclusion of BSV on F and weight as a covariate on V improved the model. Inclusion of pre-antivenom concentrations or different batches on BSV of F did not. Final model parameter estimates were CL,0.078 L h(-1), V,2.2L, Q,0.178 L h(-1) and VP,8.33L. The median half-life of distribution was 4.6 h (10-90%iles:2.6-7.1 h) and half-life of elimination, 140 h (10th-90th percentilesx:95-223h).
  
  
  CONCLUSIONS
  Indian F(ab')2 snake antivenom displayed biexponential disposition pharmacokinetics, with a rapid distribution half-life and more prolonged elimination half-life.
authors.affiliation: Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales, Australia; South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Geoffrey K
authors.initials: GK
authors.lastname: Isbister
authors.affiliation: Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales, Australia; South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Kalana
authors.initials: K
authors.lastname: Maduwage
authors.affiliation: Clinical Toxicology Research Group, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Ana
authors.initials: A
authors.lastname: Saiao
authors.affiliation: South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka; Clinical Pharmacology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Buckley
authors.affiliation: South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka; Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
authors.forename: Shaluka F
authors.initials: SF
authors.lastname: Jayamanne
authors.affiliation: South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Shahmy
authors.initials: S
authors.lastname: Seyed
authors.affiliation: South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka; Clinical Pharmacology, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Fahim
authors.initials: F
authors.lastname: Mohamed
authors.affiliation: South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Umesh
authors.initials: U
authors.lastname: Chathuranga
authors.affiliation: School of Electrical Engineering and Computer Science, University of Newcastle, Newcastle, New South Wales, Australia.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Mendes
authors.affiliation: District Hospital Hingurakgoda, Hingurakgoda, Sri Lanka.
authors.forename: Chandana
authors.initials: C
authors.lastname: Abeysinghe
authors.affiliation: General Hospital Matara, Matara, Sri Lanka.
authors.forename: Harindra
authors.initials: H
authors.lastname: Karunathilake
authors.affiliation: South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka.
authors.forename: Indika
authors.initials: I
authors.lastname: Gawarammana
authors.affiliation: Clinical Sciences and International Public Health, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
authors.affiliation: South Asian Clinical Toxicology Research Collaboration (SACTRC), Faculty of Medicine, University of Peradeniya, Peradeniya, Sri Lanka; Department of Medicine, Faculty of Medicine, University of Kelaniya, Ragama, Sri Lanka.
authors.forename: H Janaka
authors.initials: HJ
authors.lastname: de Silva
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000997:Antivenins / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D005260:Female; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D017840:Daboia / Q000502:physiology*; D012909:Snake Bites / Q000188:drug therapy* / Q000276:immunology; D013188:Sri Lanka; D014757:Viper Venoms / Q000037:antagonists & inhibitors* / Q000276:immunology
chemical_list: D000997:Antivenins; D007140:Immunoglobulin Fab Fragments; D014757:Viper Venoms