Suchaya Sanhajariya (1,2), Geoffrey K Isbister (1), Stephen B Duffull (2)
(1) Clinical Toxicology Research Group, University of Newcastle, New South Wales, Australia; (2) Otago Pharmacometrics Group, School of Pharmacy, University of Otago, Dunedin, New Zealand
Introduction: Red-bellied black snake (RBBS; Pseudechis porphyriacus) envenomation can cause systemic myotoxicity with increased serum creatine kinase (CK) concentrations greater than 1000 U/L [1]. An understanding of the time course of venom concentrations and serum CK is required to determine appropriate observation times to rule out myotoxicity in non-envenomated patients, and the effective time period for the administration of antivenom (AV).
Objectives: The aim of this study is to develop a pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PKPD) model:
(1) to describe the time course of venom exposure after bite,
(2) to describe the release of CK in patients who have been envenomated by RBBS and who have developed mild to severe myotoxicity, and
(3) to investigate the influence of AV on CK release.
Methods: Data were accessed from the Australian Snakebite Project database, a multicentre prospective observational study that recruits patients with suspected or confirmed envenomation from over 100 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 concentration. Data were available both pre- and post- administration of antivenom. Population PK and PKPD models were developed and parameters were estimated using NONMEM 7.3. For PopPK modelling, one-, two- and three- compartment models with first-order absorption and first-order or nonlinear elimination were investigated. As the dose of venom is unknown, the relative bioavailability F1 was fixed to 1 and between subject variability was estimated to account for different relative doses for each patient. Due to insufficient data in the absorption phase, the ka was fixed to 8.3h-1, to provide similar timing of the peak concentration (as per [2]). Presence of AV was accounted for as a primary covariate, where the CL post-AV was set to be 10-fold higher based on the observation that venom concentrations are reported to be undetectable shortly following AV administration [3]. Effects of other covariates including sex and age were also investigated. A PKPD model was developed using a sequential approach, where the population PK parameters of final PK model were fixed and PD parameters were estimated. A delayed increase in CK is noted during data visualisation. A turnover model for CK with a transit compartment model was used for describing the movement of CK from muscle to plasma.
Results: 116 out of 223 patients extracted had both PK and PD data suitable for model development. Of these, 28 patients developed myotoxicity (defined as CK > 1000 U/L). A total of 466 venom and 596 CK concentrations were available. A one-compartment model with first-order absorption and first-order elimination best described the venom concentration data. Nine patients show double peak profile. A model for double peak was developed but it did not improve the model fit. The elimination half-life of snake venom was calculated to be approximately 4 h, which is faster than previously reported values of 10 hours [4], although other studies have reported half-lives from 5-16 h [5, 6]. A turnover model with extended transit compartments (n=3) best described the delayed effect between venom concentration and CK profile. Our PKPD model is able to capture the release of CK following the envenomation. The peak CK concentration is noted at approximately 50 hours and the elimination half-life of CK is calculated to be approximately 40 hours which is similar to reported half-life of CK of 1.5 days [7]. Finally, it is noted that the timing of AV administration may have an influence on the extent of CK release and is the subject of future work.
Conclusion: The PK and PKPD models developed in this study were able to describe the venom and CK profile in patients with myotoxicity following RBBS envenomation. The model will guide clinicians in determining how long post-bite antivenom remains effective and how long patients require observation untreated to be confident myotoxicity will not develop.
References:
[1] Churchman, A., et al., Clinical effects of red-bellied black snake (Pseudechis porphyriacus) envenoming and correlation with venom concentrations: Australian Snakebite Project (ASP-11). The Medical Journal of Australia, 2010. 193(11-12): p. 696-700.
[2] Hart, A.J., et al., Pharmacokinetics and pharmacodynamics of the myotoxic venom of Pseudechis australis (mulga snake) in the anesthetised rat. Clinical Toxicology, 2014. 52(6): p. 604-610.
[3] Allen, G.E., et al., Clinical Effects and Antivenom Dosing in Brown Snake (Pseudonaja spp.) Envenoming – Australian Snakebite Project (ASP-14). PLoS ONE, 2012. 7 (12) (no pagination)(e53188).
[4] Sanhajariya, S., S.B. Duffull, and G.K. Isbister, Pharmacokinetics of Snake Venom. Toxins, 2018. 10(2): p. 73.
[5] Audebert, F., et al., Quantitation of venom antigens from European vipers in human serum or urine by ELISA. Journal of Analytical Toxicology, 1993. 17(4): p. 236-40.
[6] Audebert, F., et al., Viper bites in France: clinical and biological evaluation; kinetics of envenomations. Human & Experimental Toxicology, 1994. 13(10): p. 683-8.
[7] Poels, P.J.E. and F.J.M. Gabreëls, Rhabdomyolysis: a review of the literature. Clinical Neurology and Neurosurgery, 1993. 95(3): p. 175-192.
Reference: PAGE () Abstr 9356 [www.page-meeting.org/?abstract=9356]
Poster: Oral: Drug/Disease Modelling