Background: Red-bellied black snake (RBBS; Pseudechis porphyriacus) envenomation can cause systemic myotoxicity, which is characterised by elevated serum creatine kinase (CK) concentrations greater than 1,000 U/L. An understanding of the time course of venom concentrations and serum CK is useful for developing treatment plans for envenomed patients.
Aims: This study aims to 1) determine whether venom (a mixture of toxins) concentration is an appropriate driver for myotoxicity following RBBS envenomation, and 2) whether information on venom or toxin alone is sufficient to describe the occurrence of myotoxicity.
Methods: Data were extracted from the Australian Snakebite Project database, which recruits snakebites from over 200 hospitals across Australia (Ethics approvals gained from all institutions). The PK data were timed snake venom concentrations and the PD data were timed creatine kinase concentrations. Data were available both pre- and post- antivenom administration. Patients have been categorised into three groups based on degree of CK elevation [no myotoxicity (<1,000 U/L), mild (1,000-10,000 U/L) and severe >10,000 U/L)]. A population PKPD model was developed to describe the relationship between the time course of venom (a mixture of toxins) and effect (elevated CK). In addition, a KPD model was developed to describe relationship between time course of a theoretical toxin and effect. Model development and parameter estimation was performed using NONMEM v7.3. The PKPD model was developed using the PPP&D sequential approach (1). A turnover model for CK with a slow input described by a transit compartment model was used for describing the movement of CK from muscle to plasma. To address Aim 1, one thousand patient PK profiles of venom and toxin were simulated under final PK and KPD model, respectively and compared against each other. To address Aim 2, different linker models (e.g. Linear, log linear, quadratic, exponential, Emax, Sigmoid Emax) were evaluated to describe the relationship between venom or toxin exposure and the time-course of CK.
Results: Data from 114 patients were available (median age 41, 2-90y; 80 male). A turnover model with extended transit compartments (n=3) best described the delayed effect between venom or toxin concentration and CK release from myocytes. The PK profile of venom simulated under the PK model was not the same as the imputed time course of the theoretical toxin simulated under KPD model. The half-life of venom was 5.3 hours (PK) whereas half-life of the theoretical toxin was 11 hours (KPD). In this study, we found that there was no single set of linker model parameters that were able to describe the relationship between the venom or theoretical toxin exposure and the different profiles of CK for the three levels. However, when the linker model parameters were estimated separately for each CK level (mild, moderate, severe) then the linear linker function performed well for the KPD model but no set of parameters supported the PKPD model.
Conclusion: The venom concentration (a mixture of toxins) did not appear to be an appropriate driver for the extent of elevation in CK following envenomation from red-bellied black snake. A putative toxin component of the venom with a half-life of more than double the venom itself seems to be a better driver. It is not possible to determine the extent of CK elevation following envenomation from the venom (or putative toxin) profile alone and other factors (e.g. patient sensitivity or differences in venom composition between snakes) need to be determined to understand the risk.
Reference
1. Zhang L, Beal SL, Sheiner LB. Simultaneous vs. Sequential Analysis for Population PK/PD Data I: Best-Case Performance. Journal of Pharmacokinetics and Pharmacodynamics. 2003;30(6):387-404.