7 research outputs found
Population pharmacokinetics of an Indian F(ab')₂ snake antivenom in patients with Russell's viper (<i>Daboia russelii</i>) bites
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. Methods/Principal Findings: Patient data and serial blood samples were collected from patients with Russell’s viper (<i>Daboia russelii</i>) 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(V<sub>P</sub>). 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 V<sub>P</sub>,8.33L. The median half-life of distribution was 4.6h (10-90%iles:2.6-7.1h) and half-life of elimination, 140h (10<sup>th</sup>-90<sup>th</sup> percentilesx:95-223h). Conclusion: Indian F(ab’)₂ snake antivenom displayed biexponential disposition pharmacokinetics, with a rapid distribution half-life and more prolonged elimination half-life
Plots of antivenom concentration versus time for 1000 patients simulated from the final model individual predicted patient parameters for patients given two doses of antivenom, the first given 10 vials over 1 hour and then repeated at 6 hours (A) and the second given 10 vials over 1 hour and then repeated at 12 hours (B), showing median, 10% and 90% percentile concentrations.
<p>The two regimens with repeat doses are compared to a single dose in Panel C.</p
Plots of the observed antivenom concentration (μg/ml) versus time for patients given a single dose of antivenom (A), and for patients given multiple antivenom doses (B).
<p>Plots of the observed antivenom concentration (μg/ml) versus time for patients given a single dose of antivenom (A), and for patients given multiple antivenom doses (B).</p
Demographics and clinical information of 75 patients who were administered Indian antivenom, including clinical features of envenoming, treatment and outcomes.
<p>* Samples with antivenom measured in them from a total of 510 samples, 128 had no detectable antivenom;</p><p><sup>†</sup> Russell’s viper venom only detectable in 53 patients; 20WBCT– 20 minute whole blood clotting test.</p><p>Demographics and clinical information of 75 patients who were administered Indian antivenom, including clinical features of envenoming, treatment and outcomes.</p
Parameter estimates using Monolix version 4.2.
<p>CL = clearance, V = volume of the central compartment, Q = intercompartmental clearance, Vp = volume of the peripheral compartment, fwt = effect of weight on V, F = relative bioavailability.</p><p>Parameter estimates using Monolix version 4.2.</p