Recurrence phenomena after immunoglobulin therapy for snake envenomations: Part 1. Pharmacokinetics and pharmacodynamics of immunoglobulin antivenoms and related antibodies

The production of immunoglobulin antivenoms has evolved over the past 50 years, resulting in a choice of source animals and highly purified, target-specific immunoglobulin fragments (IgG, Fab(2), and Fab). Differences in pharmacokinetic and pharmacodynamic properties of these fragments may affect clinical efficacy. For example, both local and systemic recurrences (worsening after initial improvement) with intact or fragmented immunoglobulin antivenoms have been observed. Local recurrence may result in greater tissue injury, and coagulopathic recurrence may result in the risk of hemorrhage. The latter is of particular concern because coagulopathic recurrence usually occurs after patient discharge. Similar phenomena of symptom recurrence have been observed with ovine, digoxin-specific Fab, and with Fab(2) and IgG antivenoms from a variety of source animals as well. Recurrence of venom effects in Fab-treated patients appears to be the result of a pharmacokinetic and pharmacodynamic mismatch between the antivenom and target venom components. That is, tissue penetration and venom neutralization is incomplete, and clearance of unbound antivenom (antivenom that has not bound its venom target) is significantly faster than the clearance of some venom components, allowing signs and symptoms of envenomation to recur. Understanding the relative kinetics and dynamics of immunoglobulins and their targets may allow the physician to anticipate their clinical implications and may suggest modifications of the drug or dose to produce better clinical results.