based on the appearance of a significant increase in body temperature (rabbits only), 21or a positive serum PA signal

based on the appearance of a significant increase in body temperature (rabbits only), 21or a positive serum PA signal. 16 mg/kg in humans provided exposure past 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. == Study Highlights == == WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? == Drug approval under the FDA’s Pet Rule is rare and obiltoxaximab is the second monoclonal antibody developed under this pathway. There is a paucity of knowledge on the approaches to human dose selection intended for products whose efficacy cannot be tested in human clinical trials. == WHAT QUESTION DID THIS STUDY ADDRESS? == Selection of the human dose of obiltoxaximab intended for the treatment of inhalational anthrax. == WHAT THIS STUDY ADDS TO OUR KNOWLEDGE == Our study shows an approach and provides sound justification that a 16 mg/kg dose of obiltoxaximab will produce clinical benefit in the treatment of humans with inhalational anthrax. == HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE == Our approach could help guide human dose selection intended for other products being developed under the Pet Rule. Anthrax is an acute infectious disease caused byBacillus anthracis, a Grampositive, aerobic, encapsulated, endosporeforming, toxinproducing, rodshaped bacterial pathogen. 1, 2The incidence of naturally acquired anthrax is rare; however , B. anthracisspores are readily bioweaponized. 3, 4Bacillus anthracishas been identified as a toppriority, Category A biowarfare threat by the US Department of Homeland Security because it can be easily spread and causes severe illness or death. 5In 2001, the intentional delivery ofB. anthracisspores through the US Postal Service resulted in 22 cases of anthrax disease (11 inhalational, 11 cutaneous). Of those who developed inhalational anthrax, five (45%) died despite appropriate, intense care. 6 Obiltoxaximab is a chimeric immunoglobulin G1() monoclonal antibody (mAb) that binds and neutralizes protective antigen (PA), which plays a central role in anthrax toxin assembly and target cell intoxication. 7, 8Since definitive human efficacy studies withB. anthracisare not ethical and field trials to study effectiveness have not been feasible, obiltoxaximab was developed under the US Food and Drug Administration’s (FDA) Pet Rule regulations (21 CFR 601. 90), under which a drug can be approved using efficacy studies in animals and safety studies in healthy humans. Intended for the Animal Rule to apply, four criteria need to be met: i) a reasonably wellunderstood pathophysiological mechanism of the toxicity of the material and its prevention or substantial reduction by the product; ii) the effect is demonstrated in more than one animal species expected to react with a response predictive intended for humans; iii) the animal study end point AMD 3465 Hexahydrobromide is clearly related to the desired benefit in humans; and iv) the data on the pharmacokinetics (PK) and pharmacodynamics (PD) of the product or other relevant data or information, in animals and humans, allows selection of an effective dose in humans. 9, 10 Obiltoxaximab continues to be extensively studied in both AMD 3465 Hexahydrobromide humans and animals. Human PK data from five controlled studies in over 500 healthy volunteers demonstrated that obiltoxaximab publicity increased proportionally with dose, had a halflife of 1723 days, and that it was safe and generally AMD 3465 Hexahydrobromide welltolerated. 11The pet models (New Zealand White (NZW) rabbits and cynomolgus macaques) intended for investigating anthrax disease progression after inhalational exposure to anthrax spores are well established and correlate well with the pathophysiology of the disease manifested in humans. 12, 13, 14A series of randomized, placebocontrolled, CD86 parallelgroup, doseranging, triggertotreat studies in which obiltoxaximab was administered as an intravenous (i. v. ) bolus to NZW rabbits and cynomolgus macaques were conducted to describe the PD and efficacy of obiltoxaximab. The results demonstrated the survival efficacy of obiltoxaximab at 16 mg/kg. 15 Obiltoxaximab pharmacological activity is based on neutralization of circulating PA. 8, 16, 17During the course of inhalational anthrax, bacteremia and toxemia correlate18and are affordable measures of disease progression. 19, 20In animal treatment studies, obiltoxaximab administration resulted in serum PA concentrations below the lower limit of assay quantification ( <9. 68 ng/mL) at the earliest posttreatment time point measured (as early as 15 min in some studies) in both surviving and nonsurviving animals. 15 This report describes our approach for the selection and justification of the clinical dose of obiltoxaximab for treatment of inhalational anthrax in humans AMD 3465 Hexahydrobromide based on translation of efficacy, AMD 3465 Hexahydrobromide PK, and PD data from healthy and infected pet studies to humans using observed data and simulations based on validated population PK and survival models. 11, 15 == MATERIALS AND METHODS == == Study designs and treatments == == Pet pharmacokinetic studies == Two NZW rabbit studies (one each in unexposed andB. anthracisinfected animals) and five cynomolgus macaque studies (one in unexposed and four in infected.