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Snakebite envenomation is responsible for over 100,000 deaths and 400,000 cases of disability annually, most of which are preventable through access to safe and effective antivenoms. Snake venom toxins span a wide molecular weight range, influencing their absorption, distribution, and elimination within the body. In recent years, a range of scaffolds have been applied to antivenom development. These scaffolds similarly span a wide molecular weight range and subsequently display diverse pharmacokinetic behaviours. Computational simulations represent a powerful tool to explore the interplay between these varied antivenom scaffolds and venoms, to assess whether a pharmacokinetically optimal antivenom exists. The purpose of this study was to establish a computational model of systemic snakebite envenomation and treatment, for the quantitative assessment and comparison of conventional and next-generation antivenoms. A two-compartment mathematical model of envenomation and treatment was defined and the system was parameterised using existing data from rabbits. Elimination and biodistribution parameters were regressed against molecular weight to predict the dynamics of IgG, F(ab') 2 , Fab, scFv, and nanobody antivenoms, spanning a size range of 15–150 kDa. As a case study, intramuscular envenomation by Naja sumatrana (equatorial spitting cobra) and its treatment using Fab, F(ab') 2 , and IgG antivenoms was simulated. Variable venom dose tests were applied to visualise effective antivenom dose levels. Comparisons to existing antivenoms and experimental rescue studies highlight the large dose reductions that could result from recombinant antivenom use. This study represents the first comparative in silico model of snakebite envenomation and treatment. [Display omitted] • We built an in silico model of systemic snake envenomation and treatment to compare the efficacy of different antivenoms. • The pharmacokinetics of five antivenoms (IgG, F(ab') 2 , Fab, scFv, Nanobody) were predicted based on molecular weight. • Intramuscular envenomation by the elapid Naja sumatrana and treatment with Fab, F(ab') 2 , and IgG antivenoms was simulated. • Compartmental simulations demonstrate the large dose reductions that could result from adoption of recombinant antivenoms. [ABSTRACT FROM AUTHOR]

In recent years it has become possible to design snakebite antivenoms with diverse pharmacokinetic properties. Owing to the pharmacokinetic variability of venoms, the choice of antivenom scaffold may influence a treatment's neutralisation coverage. Computation offers a useful medium through which to assess the pharmacokinetics and pharmacodynamics of envenomation-treatment systems, as antivenoms with identical neutralising capacities can be simulated. In this study, we simulate envenomation and treatment with a variety of antivenoms, to define the properties of effective antivenoms. Systemic envenomation and treatment were described using a two-compartment pharmacokinetic model. Treatment of Naja sumatrana and Cryptelytrops purpureomaculatus envenomation was simulated with a set of 200,000 theoretical antivenoms across 10 treatment time delays. These two venoms are well-characterised and have differing pharmacokinetic properties. The theoretical antivenom set varied across molecular weight, dose, k on , k off , and valency. The best and worst treatments were identified using an area under the curve metric, and a global sensitivity analysis was performed to quantify the influence of the input parameters on treatment outcome. The simulations show that scaffolds of diverse molecular formats can be effective. Molecular weight and valency have a negligible direct impact on treatment outcome, however low molecular weight scaffolds offer more flexibility across the other design parameters, particularly when treatment is delayed. The simulations show k on to primarily mediate treatment efficacy, with rates above 105 M−1s−1 required for the most effective treatments. k off has the greatest impact on the performance of less effective scaffolds. While the same scaffold preferences for improved treatment are seen for both model snakes, the parameter bounds for C. purpureomaculatus envenomation are more constrained. This paper establishes a computational framework for the optimisation of antivenom design. [Display omitted] • We used a computational model to identify the pharmacokinetic and pharmacodynamic properties of effective antivenoms. • We explored the effect of varying antivenom size, affinity, valency, dose, as well as treatment time and venom type. • Global parameter optimisation and global sensitivity analysis highlight the primary importance of antivenom k on. • Molecular size has a limited direct impact on treatment outcome, but small scaffolds perform better in delayed treatment. • Model viper and elapid envenomation cases show similar antivenom design preferences. [ABSTRACT FROM AUTHOR]