Exposure-Response Modeling and Simulation to Support Human Dosing of Botulism Antitoxin Heptavalent Product

Martin Beliveau, Deborah Anderson, Doug Barker, Shantha Kodihalli, Emilie Simard, Christine Hall, Jason S Richardson, Martin Beliveau, Deborah Anderson, Doug Barker, Shantha Kodihalli, Emilie Simard, Christine Hall, Jason S Richardson

Abstract

Botulism antitoxin heptavalent (A, B, C, D, E, F, and G - Equine; BAT) product is a sterile solution of F(ab')2 and F(ab')2 -related antibody fragments prepared from plasma obtained from horses that have been immunized with a specific serotype of botulinum toxoid and toxin. BAT product is indicated for the treatment of symptomatic botulism following documented or suspected exposure to botulinum neurotoxin serotypes A to G in adults and pediatric patients. Pharmacokinetic and exposure-response models were used to explore the relationship between BAT product exposure and the probability of survival, and the occurrence of relevant moderate clinical signs observed during the preclinical development of BAT product to justify the clinical dose. The predicted probability of survival in humans for all serotypes of botulinum neurotoxin was more than 95.9% following intravenous administration of one vial of BAT product. Furthermore, this BAT product dose is expected to result in significant protection against clinical signs in human adults for all botulinum neurotoxin serotypes. Our exposure response model indicates that we have sufficient antitoxin levels to give full protection at various theoretical exposure levels and, based on neutralization capacity/potency of one dose of BAT product, it is expected to exceed the amount of circulating botulinum neurotoxin.

Conflict of interest statement

D.A., D.B., S.K., C.H., and J.S.R. are currently employees and stockholders of Emergent BioSolutions. All other authors declared no competing interests for this work.

© 2022 Emergent Biodefense. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Figures

Figure 1
Figure 1
Comparison of profiles of BAT product antitoxin serotypes B and E in guinea pigs. Filled symbols represent observed pharmacokinetic (PK) values following a high dose of BAT product, whereas empty symbols represent observed PK values following a low dose of BAT product. Lines represent mean data. BAT, botulism antitoxin heptavalent.
Figure 2
Figure 2
Mean concentration of BAT product antitoxin serotype A in nonhuman primates (NHP) with and without neurotoxin. Filled symbols represents the prolongation of half‐life observed when BAT product is administered in presence of neurotoxin serotype A. BAT, botulism antitoxin heptavalent.
Figure 3
Figure 3
Logistic regression of antitoxin concentration of BAT product serotype A vs. survival. Black symbols represent individual observed data (0 for not survived; 1 for survived). Grey symbols represent observed probability composite from the individual data. Black line represents model fit of the probability data, whereas black dotted line represents confidence interval. Grey dotted lines represents the 80% survival reference (target survival rate) leading to the area under the curve that is defined as the minimum efficacious exposure (MEE). See Emanuel et al. and Kodihalli et al. for study details and a description of the experimental data used in the regression analysis. Probabilities of 0 and 1 were offset to improve data visualization. GP, guinea pig.

References

    1. Arnon, S.S. Botulinum toxin as a biological weapon: medical and public health management. JAMA J. Am. Med. Assoc. 285, 1059–1070 (2001).
    1. Rotz, L.D. & Hughes, J.M. Advances in detecting and responding to threats from bioterrorism and emerging infectious disease. Nat. Med. 10, S130–S136 (2004).
    1. Hatheway, C.L. Botulism: the present status of the disease. Curr. Top. Microbiol. Immunol. 195, 55–75 (1995).
    1. Zhang, S. et al. Identification and characterization of a novel botulinum neurotoxin. Nat. Commun. 8, 14130 (2017).
    1. Montecucco, C. , Rossetto, O. & Schiavo, G. Presynaptic receptor arrays for clostridial neurotoxins. Trends Microbiol. 12, 442–446 (2004).
    1. Montal, M. Botulinum neurotoxin: a marvel of protein design. Annu. Rev. Biochem. 79, 591–617 (2010).
    1. Gangarosa, E.J. et al. Botulism in the United States, 1899–1969. Am. J. Epidemiol. 93, 93–101 (1971).
    1. Shapiro, R.L. , Hatheway, C. & Swerdlow, D.L. Botulism in the United States: a clinical and epidemiologic review. Ann. Intern. Med. 129, 221–228 (1998).
    1. Centers for Disease Control and Prevention (CDC) . Investigational heptavalent botulinum antitoxin (HBAT) to replace licensed botulinum antitoxin AB and investigational botulinum antitoxin E. MMWR Morb. Mortal. Wkly. Rep. 59, 299 (2010).
    1. Arnon, S.S. , Schechter, R. , Maslanka, S.E. , Jewell, N.P. & Hatheway, C.L. Human botulism immune globulin for the treatment of infant botulism. N. Engl. J. Med. 354, 462–471 (2006).
    1. Chang, G.Y. & Ganguly, G. Early antitoxin treatment in wound botulism results in better outcome. Eur. Neurol. 49, 151–153 (2003).
    1. Dolman, C.E. & Iida, H. Type E botulism: its epidemiology, prevention and specific treatment. Can. J. Public Heal. Rev. Can. Santé Publique 54, 293–308 (1963).
    1. Kongsaengdao, S. et al. An outbreak of botulism in Thailand: clinical manifestations and management of severe respiratory failure. Clin. Infect. Dis. 43, 1247–1256 (2006).
    1. Offerman, S.R. , Schaefer, M. , Thundiyil, J.G. , Cook, M.D. & Holmes, J.F. Wound botulism in injection drug users: time to antitoxin correlates with intensive care unit length of stay. West. J. Emerg. Med. 10, 251–256 (2009).
    1. Tacket, C.O. , Shandera, W.X. , Mann, J.M. , Hargrett, N.T. & Blake, P.A. Equine antitoxin use and other factors that predict outcome in type A foodborne botulism. Am. J. Med. 76, 794–798 (1984).
    1. Richardson, J.S. et al. Safety and clinical outcomes of an equine‐derived heptavalent botulinum antitoxin treatment for confirmed or suspected botulism in the United States. Clin. Infect. Dis. 70, 1950–1957 (2020).
    1. Parrera, G.S. et al. Use of botulism antitoxin heptavalent (A, B, C, D, E, F, G)—(Equine) (BAT®) in clinical study subjects and patients: a 15‐year systematic safety review. Toxins (Basel). 14, 19 (2021).
    1. Emanuel, A. et al. Efficacy of equine botulism antitoxin in botulism poisoning in a guinea pig model. PLoS One 14, e0209019 (2019).
    1. Kodihalli, S. et al. Therapeutic efficacy of equine botulism antitoxin in Rhesus macaques. PLoS One 12, e0186892 (2017).
    1. Carlella, M.A. Botulinum toxoids. In: Botulism Proc. a Symp. (Lewis KH) 113–130 (Government Printing Office: PHS Publication, Washington, DC, 1964).
    1. FDA BAT (Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) ‐ (Equine). (2018) <>.
    1. Gabrielsson, J. & Weiner, D. Pharmacokinetic and Pharmacodynamic Data Analysis – Concepts and Applications (Swedish Pharmaceutical Society, Stockholm, 2016).
    1. Agoram, B.M. Use of pharmacokinetic/ pharmacodynamic modelling for starting dose selection in first‐in‐human trials of high‐risk biologics. Br. J. Clin. Pharmacol. 67, 153–160 (2009).
    1. Overgaard, R. , Ingwersen, S. & Tornøe, C. Establishing good practices for exposure‐response analysis of clinical endpoints in drug development. CPT Pharmacometrics Syst. Pharmacol. 4, 565–575 (2015).
    1. Hatheway, C. , Snyder, J. , Seals, J. , Edell, T. & Lewis, G. Antitoxin levels in botulism patients treated with trivalent equine botulism antitoxin to toxin types A, B, and E. J. Infect. Dis. 150, 407–412 (1984).
    1. Ball, A. et al. Human botulism caused by Clostridium botulinum type E: the Birmingham outbreak. Q. J. Med. 48, 473–491 (1979).
    1. Chertow, D. et al. Botulism in 4 adults following cosmetic injections with an unlicensed, highly concentrated botulinum preparation. JAMA J. Am. Med. Assoc. 296, 2476–2479 (2006).
    1. Ravichandran, E. et al. An initial assessment of the systemic pharmacokinetics of botulinum toxin. J. Pharmacol. Exp. Ther. 318, 1343–1351 (2006).
    1. Davies, B. & Morris, T. Physiological parameters in laboratory animals and humans. Pharm. Res. 10, 1093–1095 (1993).
    1. Li, Z. , Krippendorff, B.‐F. & Shah, D.K. Influence of molecular size on the clearance of antibody fragments. Pharm. Res. 34, 2131–2141 (2017).
    1. Cao, Y. , Balthasar, J.P. & Jusko, W.J. Second‐generation minimal physiologically‐based pharmacokinetic model for monoclonal antibodies. J. Pharmacokinet. Pharmacodyn. 40, 597–607 (2013).
    1. Bonifacio, L. et al. Target‐mediated drug disposition pharmacokinetic/pharmacodynamic model‐informed dose selection for the first‐in‐human study of AVB‐S6‐500. Clin. Transl. Sci. 13, 204–211 (2020).
    1. Mahmood, I. A Single animal species‐based prediction of human clearance and first‐in‐human dose of monoclonal antibodies: beyond monkey. Antibodies 10, 35 (2021).
    1. Wang, W. & Prueksaritanont, T. Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited. Biopharm. Drug Dispos. 31, 253–263 (2010).
    1. Ling, J. , Zhou, H. , Jiao, Q. & Davis, H.M. Interspecies scaling of therapeutic monoclonal antibodies: initial look. J. Clin. Pharmacol. 49, 1382–1402 (2009).

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