Population pharmacokinetics of Pseudechis porphyriacus (red-bellied black snake) venom in snakebite patients

Abstract

Objectives

Understanding the time course of venom exposure in snakebite patients is important for the optimisation of treatment including antivenom dose and timing. We aimed to investigate the pharmacokinetics of red-bellied black snake (RBBS; Pseudechis porphyriacus) venom in envenomed patients.

Methods

Timed venom concentration data were obtained from patients with RBBS envenomation recruited to the Australian Snakebite Project (ASP), including demographics and antivenom treatment. Venom concentrations were measured using an enzyme immunoassay. Data were modelled using NONMEM version 7.3. Uncertainty in venom “dose” was accounted for by arbitrarily fixing the average amount to 1 mg and incorporating between-subject variability on relative bioavailability. A scale parameter for venom clearance was implemented to account for the rapid venom clearance following antivenom dosing. A sensitivity analysis was performed to determine the magnitude of venom clearance amplification.

Results

There were 457 venom concentrations in 114 patients (median age 41, 2–90 y; 80 male). Antivenom was administered to 54 patients a median of 4.2 h post-bite (0.67 to 32 h). A one-compartment model with first-order absorption and elimination provided the best description of the data. The estimated clearance and volume of distribution were 5.21 L/h and 39.9 L, respectively. The calculated elimination half-life of P. porphyriacus venom from the final pharmacokinetic model was 5.35 ± 0.36 h. The variability in the relative dose of injected venom was 140%. Antivenom administration increased venom clearance by 40-fold. Ten patients showed evidence of a double peak in the absorption profile.

Conclusion

The information on the exposure time of venom in the body following envenomation will help improve treatment and the timing of antivenom.

Keywords:

• Snake venom
• pharmacokinetics
• Pseudechis porphyriacus
• red-bellied black snake
• antivenom

Acknowledgements

The authors would like to thank the numerous medical, nursing and laboratory staff around Australia for their supports in recruiting patients, collecting samples and making Australian Snakebite Project possible. We also acknowledge the research administrative staff at the Clinical Toxicology Research Group for their assistance with patient data collection and entry. We thank Margaret O'Leary and Kellie Fakes for performing the venom assays.

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

S.S. is supported by the Australian Government Research Training Program Scholarship. G.K.I. is supported by a National Health and Medical Research Council Senior Research Fellowship, ID1061041. The Australian Snakebite Project is funded by a National Health and Medical Research Council Centre for Research Excellence (ID 1110343).