Intravenous Vipera berus Venom-Specific Fab Fragments and Intramuscular Vipera ammodytes Venom-Specific F(ab’)2 Fragments in Vipera ammodytes-Envenomed Patients

Abstract

Vipera ammodytes (V. ammodytes) is the most venomous European viper. The aim of this study was to compare the clinical efficacy and pharmacokinetic values of intravenous Vipera berus venom-specific (paraspecific) Fab fragments (ViperaTAb) and intramuscular V. ammodytes venom-specific F(ab’)2 fragments (European viper venom antiserum, also called “Zagreb” antivenom) in V.ammodytes-envenomed patients. This was a prospective study of V.ammodytes-envenomed patients that were treated intravenously with ViperaTAb or intramuscularly with European viper venom antiserum that was feasible only due to the unique situation of an antivenom shortage. The highest venom concentration, survival, length of hospital stay and adverse reactions did not differ between the groups. Patients treated with intravenous Fab fragments were sicker, with significantly more rhabdomyolysis and neurotoxicity. The kinetics of Fab fragments after one or more intravenous applications matched better with the venom concentration in the early phase of envenomation compared to F(ab’)2 fragments that were given intramuscularly only on admission. F(ab’)2 fragments given intramuscularly had 25-fold longer apparent total body clearance and 14-fold longer elimination half-time compared to Fab fragments given intravenously (2 weeks vs. 24 hours, respectively). In V.ammodytes-envenomed patients, the intramuscular use of specific F(ab’)2 fragments resulted in a slow rise of antivenom serum concentration that demanded their early administration but without the need for additional doses for complete resolution of all clinical signs of envenomation. Intravenous use of paraspecific Fab fragments resulted in the immediate rise of antivenom serum concentration that enabled their use according to the clinical progress, but multiple doses might be needed for efficient therapy of thrombocytopenia due to venom recurrence, while the progression of rhabdomyolysis and neurotoxic effects of the venom could not be prevented.

Snake Antivenoms—Toward Better Understanding of the Administration Route

“…Although highly needed, studies on healthy volunteers and envenomed patients ( Table 2 ) are scarce and often flawed [ 47 ], providing insufficient data for unambiguous conclusions about the most efficient application strategy against snakebite envenoming [ 134 ]. In the vast majority of cases, they are performed in uncontrolled setting frequently including only individual cases [ 17 , 136 , 137 , 138 ] or groups small in the number of participants [ 45 , 46 , 124 , 139 , 140 ]. Often, there are situations where the species responsible for the envenomation could not have been reliably identified and the treatment could be suspected only from the patient’s description or the clinical signs, mostly coagulopathy as the most common one [ 2 , 45 , 46 , 134 ], which calls into question the appropriateness of the applied antivenom’s specificity and, consequently, the degree of its efficacy.…”

“…Often, there are situations where the species responsible for the envenomation could not have been reliably identified and the treatment could be suspected only from the patient’s description or the clinical signs, mostly coagulopathy as the most common one [ 2 , 45 , 46 , 134 ], which calls into question the appropriateness of the applied antivenom’s specificity and, consequently, the degree of its efficacy. Time elapsed between the snakebite incident and the therapy application usually varies between the individual cases, aggravating the comparison and interpretation of obtained results [ 45 , 94 , 138 , 140 ]. Finally, infrequent sampling during the first few hours after antivenom administration, with the majority of victims providing an inadequate number of time concentration samples [ 45 ], and an unsatisfactory long follow-up period, interrupted by the patient’s discharge from the hospital [ 140 ], represent the most common restricting factors for a proper pharmacokinetic analysis.…”

“…Time elapsed between the snakebite incident and the therapy application usually varies between the individual cases, aggravating the comparison and interpretation of obtained results [ 45 , 94 , 138 , 140 ]. Finally, infrequent sampling during the first few hours after antivenom administration, with the majority of victims providing an inadequate number of time concentration samples [ 45 ], and an unsatisfactory long follow-up period, interrupted by the patient’s discharge from the hospital [ 140 ], represent the most common restricting factors for a proper pharmacokinetic analysis. Therefore, the accomplishment of the complete picture of administration route appropriateness aims at looking at the data from animal studies in a consolidated manner with those measured in treated patients, all in view of the course of the clinical progress.…”

“…Various studies in humans have been performed with the aim to evaluate the pharmacokinetic properties of antivenoms in relation to the type of active compound they contain (IgGs, F(ab’) 2 or Fab fragments) and the route of application [ 17 , 45 , 48 , 124 , 134 , 138 , 139 , 140 ]. The kinetics of i.v.…”

“…Its elimination half-life varied between 16 and 28 h. Regarding the volume of distribution, Seifert et al [ 124 ] demonstrated that antivenom used against crotaline bite had a value of 110 mL/kg. According to two case series reports [ 138 , 140 ] that were related to the treatment of European vipers with ViperaTAb, the volume of distribution could be as large as 182–415 mL/kg and 118–524 mL/kg, respectively. The obtained results for the distribution half-life and systemic clearance appeared to be more uniform with the values in the range from 1.2 to 3.2 h [ 124 , 138 ] for the former and 4.3 to 13.4 mL/h/kg for the latter [ 124 , 138 , 140 ].…”