Project title: Pharmacokinetics of snake antivenom following intravenous and intramuscular administration in envenomed large animal model (PKSheep)

Grantor: Croatian Science Foundation

Grantor’s website: www.hrzz.hr

Principal investigator: Tihana Kurtović, PhD

Duration: 03/2021-03/2026

Research team:   Tihana Kurtović, PhD

                             Maja Lang Balija, PhD

                             Sanja Mateljak Lukačević, MSc

                              PhD student

                              Postdoctoral student

Total funding: 1.990.000,00 HRK

Brief description:

Parenteral administration of antivenoms (AVs) is the mainstay in the snakebite envenoming therapy. Impact of the administration route on their effectiveness has never been systematically investigated. Until recently, AV pharmacokinetics was followed in the systemic circulation only, mostly using animal models. I.m. AV seems unadjusted in time and dose manner to the rapid appearance of venom (V) in blood. When given i.v., the whole amount of drug is straightaway available in systemic circulation, appearing more complied with V incidence. Hypothesis that i.v. route might be the better principle emerged. Our recent research on human victims also revealed differences in AV pharmacokinetics in blood when given i.v. or i.m., but they didn't appear to be relevant for therapy success. Recently, it was concluded that V neutralisation in lymphatic system might be of great importance for clinical outcome. Thus, V-AV pharmacokinetic matching in systemic circulation might not be the indicator of therapy success. Low bioavailability associated with i.m. route might be of lesser importance.

Our research will aim for revealing optimal administration route in envenoming treatment, with emphasis on V-AV interplay in lymphatic system. Pharmacokinetics of i.m. and i.v. AV will be analysed in experimentally envenomed sheep that will be subjected to the blood and lymph sampling. By performing timed level measurements, the AV effect on decrement of V quantities in both body compartments will be defined. Pharmacokinetics and neutralisation potential of i.v. and i.m. AV will be comparatively investigated for the first time. Since safety profiles of i.v. and i.m. AVs have not been simultaneously examined for now, information on anti-AV IgGs development as a mark of the approach of lower immunogenicity and improved safety will be provided. Haematological parameters will be monitored to access and compare the potential of differently applied AVs to reverse V-induced clinical symptoms.