Preclinical Evaluation of the Efficacy of Antivenoms for Snakebite Envenoming: State-of-the-Art and Challenges Ahead

Abstract

Animal-derived antivenoms constitute the mainstay in the therapy of snakebite envenoming. The efficacy of antivenoms to neutralize toxicity of medically-relevant snake venoms has to be demonstrated through meticulous preclinical testing before their introduction into the clinical setting. The gold standard in the preclinical assessment and quality control of antivenoms is the neutralization of venom-induced lethality. In addition, depending on the pathophysiological profile of snake venoms, the neutralization of other toxic activities has to be evaluated, such as hemorrhagic, myotoxic, edema-forming, dermonecrotic, in vitro coagulant, and defibrinogenating effects. There is a need to develop laboratory assays to evaluate neutralization of other relevant venom activities. The concept of the 3Rs (Replacement, Reduction, and Refinement) in Toxinology is of utmost importance, and some advances have been performed in their implementation. A significant leap forward in the study of the immunological reactivity of antivenoms against venoms has been the development of “antivenomics”, which brings the analytical power of mass spectrometry to the evaluation of antivenoms. International partnerships are required to assess the preclinical efficacy of antivenoms against snake venoms in different regions of the world in order to have a detailed knowledge on the neutralizing profile of these immunotherapeutics.

A Bayesian phase 2 model based adaptive design to optimise antivenom dosing: application to a dose-finding trial for a novel Russell’s viper antivenom in Myanmar

“…All antivenom used in the study will be provided from a single batch. The antivenom will undergo retrospective pre-clinical testing to determine the median effective dose (ED50), the gold standard pre-clinical test for assessing antivenom efficacy [29, 30]. This will allow comparison between pre-clinical testing and in vivo outcomes.…”

Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

“…WHO has provided a detailed pre-clinical assessment for antivenom development for snakebite treatment and has recently been reviewed in detail by Gutierrez et al [26,27]. However, none exists for SMT development for snakebite.…”

“…Herein, we focus on sPLA2 as a candidate for inhibition by SMTs because of its ubiquity and clinically significant effects [26,51]. Snake venom sPLA2s play roles in early-and late-onset symptomology, as well as synergistic and regulatory roles for other co-existing snake venom components [56][57][58][59][60][61][62][63].…”

“… Tested with both: o Minimum acceptable: Pre-mixing of venom and antidote prior to injection (ED50 determination) [27] o Ideal: Venom administration prior to administration of antidote [6,26,40] Broad Spectrum  Depending on target selection (ubiquity and medical importance of inhibitory target among snake species) [41,42] Heat Stable  Real-time stability studies up to 30 °C (±2 °C) and relative humidity of 75% (±5%) (WHO "Climatic Zone IVb") [ …”

Snakebites: reducing their international impact

“…These advances are embodied in WHO‐sponsored clinical management guidelines for African and South‐East Asian countries 13 , 14 . The geographic distributions of medically important snakes and their taxonomic relationships have been established, while the complexities of and geographic variations in venom composition have been clarified by the new technologies of venomics and antivenomics 15 …”