Abstract
BackgroundThere 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.Methods/Principal FindingsPatient 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 (40-70y) 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 Lh-1, V,2.2L, Q,0.178Lh-1 and VP,8.33L. The median half-life of distribution was 4.6h (10-90%iles:2.6-7.1h) and half-life of elimination, 140h (10th-90th percentilesx:95-223h).ConclusionIndian F(ab’)2 snake antivenom displayed biexponential disposition pharmacokinetics, with a rapid distribution half-life and more prolonged elimination half-life.
Highlights
Snake envenoming is a major health issue in South and South-eastern Asia [1]
In this study we measured serial antivenom concentrations in patients with Russell’s viper envenoming given antivenom. Using this data we modelled the pharmacokinetics of antivenom in the population and showed that antivenom concentrations had a bi-exponential decay with an initial decrease over 12 hours and a slow decrease over days
Snake envenoming is a common problem in Sri Lanka and large amounts of antivenom are used throughout the country each year
Summary
Snake envenoming is a major health issue in South and South-eastern Asia [1]. antivenom is the most important treatment for snake envenoming, it can cause early systemic hypersensitivity reactions [2, 3], and there is limited evidence to support currently practiced dosing schedules. Dosing and assessment of the effectiveness of antivenom in human envenoming remains controversial and treatment protocols are not based on the kinetics of venom or antivenom. There are few studies of the pharmacokinetics of antivenom, and most of these are in animals [4]. The clinical effects of envenoming in these species are generally irreversible so determining if enough antivenom has been given and deciding to re-dose is often arbitrary and not based on whether all venom has been bound, or on the pharmacokinetics of antivenom. Measurement of venom and antivenom concentrations in patients with snake bite is required to improve effective initial and repeat dosing [8]. This study aimed to investigate the pharmacokinetics of an Indian snake antivenom in humans with Russell’s viper bites
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