title: Animal-to-Human Dose Translation of Obiltoxaximab for Treatment of Inhalational Anthrax Under the US FDA Animal Rule.
abstract: Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax under the US Food and Drug Administration's (FDA) Animal Rule. The human dose was selected and justified by comparing observed obiltoxaximab exposures in healthy and infected New Zealand White rabbits and cynomolgus macaques to observed exposures in healthy humans, to simulated exposures in healthy and infected humans, and to serum PA levels in infected animals. In humans, at 16 mg/kg intravenous, obiltoxaximab AUC was >2 times that in animals, while maximum serum concentrations were comparable to those in animals and were maintained in excess of the concentration required for PA neutralization in infected animals for 2-3 weeks. Obiltoxaximab 16 mg/kg in humans provided exposure beyond that of 16 mg/kg in animals, ensuring a sufficient duration of PA neutralization to allow for adaptive immunity development. Our approach to dose translation may be applicable to other agents being developed under the Animal Rule.
authors.affiliation: Department of Clinical Operations, Elusys Therapeutics, Inc, Pine Brook, New Jersey, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Nagy
authors.affiliation: Metrum Research Group LLC, Tariffville, Connecticut, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mondick
authors.affiliation: Department of Research and Nonclinical Development, Elusys Therapeutics, Inc, Pine Brook, New Jersey, USA.
authors.forename: N
authors.initials: N
authors.lastname: Serbina
authors.affiliation: Department of Research and Nonclinical Development, Elusys Therapeutics, Inc, Pine Brook, New Jersey, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Casey
authors.affiliation: Department of Research and Nonclinical Development, Elusys Therapeutics, Inc, Pine Brook, New Jersey, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Carpenter
authors.affiliation: Metrum Research Group LLC, Tariffville, Connecticut, USA.
authors.forename: J
authors.initials: J
authors.lastname: French
authors.affiliation: Aclairo Pharmaceutical Development Group Inc, Vienna, Virginia, USA.
authors.forename: R
authors.initials: R
authors.lastname: Guttendorf
mesh_terms: D000818:Animals; D000881:Anthrax / Q000188:drug therapy*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000992:Antitoxins / Q000008:administration & dosage* / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008252:Macaca fascicularis; D011817:Rabbits; D012141:Respiratory Tract Infections / Q000188:drug therapy*; D013997:Time Factors; D057170:Translational Research, Biomedical; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000911:Antibodies, Monoclonal; D000992:Antitoxins; C000611266:obiltoxaximab