Population Pharmacokinetics of an Indian F (ab')2 Snake Antivenom in Patients with Russell's Viper (Daboia russelii) 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 (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). Conclusion Indian F(ab')2 snake antivenom displayed biexponential disposition pharmacokinetics, with a rapid distribution half-life and more prolonged elimination half-life

Isoniazid poisoning: pharmacokinetics and effect of hemodialysis in a massive ingestion

Isoniazid is a rare overdose that causes seizures and there is limited evidence to guide treatment. We report a 20-year-old female migrant who presented with recurrent seizures after ingesting 25 g of isoniazid. She was treated with activated charcoal, repeated doses of midazolam for the seizures, and given multiple doses of pyridoxine (14 mg), limited by availability. She was admitted to intensive care, and 5.5 hours post-ingestion, she was commenced on continuous veno-venous hemodiafiltration (CVVHDF). She was extubated after 24 hours and CVVHDF was ceased 6 hours later (30 hours post-overdose). Her renal function remained normal and her initial lactate was the highest at 2.3. She made a full recovery. Five plasma samples were collected before, during, and after CVVHDF, and isoniazid was quantified with liquid chromatography-tandem mass spectrometry. A pharmacokinetic analysis of time-isoniazid concentration data was fitted to a two-compartment model with first-order input (with fixed k_a) with the effect of CVVHDF modeled as a time-dependent covariate. This suggested that there was initially good clearance with CVVHDF (4 times endogenous clearance), which rapidly declined within hours

Cardiovascular toxicity with levetiracetam overdose

Objective: To describe the cardiovascular toxicity and pharmacokinetics of levetiracetam in overdose. Case Report: A 43-year-old female presented 8 h post ingestion of 60-80 g of levetiracetam with mild central nervous system depression, bradycardia, hypotension and oliguria. Her cardiovascular toxicity transiently responded to atropine and intravenous fluids. A bedside echocardiogram demonstrated normal left and right ventricular contractility. Despite her cardiovascular toxicity and oliguria, she had normal serial venous lactates and renal function; and made a complete recovery over 48 h. Her levetiracetam concentration was 463mcg/ml 8h post ingestion (therapeutic range 10-40mcg/ml) and her concentration-time data best fitted a one-compartment model with first-order input and an elimination half-life of 10.4 h. Discussion: Levetiracetam in large ingestions appears to cause bradycardia and hypotension that is potentially responsive to atropine and intravenous fluids. Based on a normal echocardiogram, the mechanism for this effect may be levetiracetam acting at muscarinic receptors at high concentration. The pharmacokinetics of levetiracetam in overdose appeared to be similar to therapeutic levetiracetam dosing

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_P). 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_P,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^th-90^th 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>^† 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