Predicting a Safe, Efficacious Human Dose for a Novel Anti-Cryptosporidiosis Therapeutic

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<b>Abstract ID 21181</b> <b>Poster Board 587</b> <b>Introduction:</b> Cryptosporidiosis, the disease caused by infection with <i>Cryptosporidium spp.</i>, can lead to long-term adverse impacts and even death in malnourished children and immunocompromised patients. Specifically, in children younger than five years old, the disease has myriad detrimental effects that include persistent diarrheal episodes and impairment in cognitive development.^1,2 The only FDA-approved treatment, nitazoxanide, is marginally effective in the populations most impacted by the disease, and new treatment options are urgently needed.³ Bumped kinase inhibitors (BKIs) represent a promising class of therapeutics that are effective against <i>Cryptosporidium</i> infection in preclinical models of disease, and BKI-1708 has emerged as a lead candidate based on its remarkable efficacy and safety profile.⁴ Here, we use preclinical efficacy, pharmacokinetic (PK), and toxicity data to identify a safe, effective dose of BKI-1708 for the treatment of <i>Cryptosporidium</i> infection in humans. <b>Methods:</b> To characterize the BKI-1708 exposure-response relationship for treatment of <i>Cryptosporidium</i> infection, <i>C. parvum</i>-infected IFN-γ^-/- mice were treated with a range of BKI-1708 doses. PK models were developed for BKI-1708 using data from PK studies and sparse PK data collected from efficacy studies. To estimate BKI-1708 PK parameters in humans, both allometric scaling and <i>in&nbsp;vitro</i> to <i>in&nbsp;vivo</i> extrapolation (IVIVE) were used. Allometric scaling was informed by BKI-1708 intravenous (IV) PK studies conducted in mice, rats, dogs, and non-human primates. IVIVE was supported by <i>in&nbsp;vitro</i> studies with hepatocytes, microsomes, and purified cytochrome P450 enzymes (CYP450s). BKI-1708 toxicity was characterized in rats and dogs after multiple-dose administration. <b>Results/Conclusion:</b> In mice, a BKI-1708 plasma concentration of 0.12 mg/mL was associated with a 90% reduction in <i>Cryptosporidium</i> oocyst shedding in feces. Allometric scaling was used to estimate a BKI-1708 plasma clearance of 5.6 L/h, volume of distribution of 67.1 L, and half-life of 8.4 hours in humans. <i>In vitro</i> studies with hepatocytes and CYP450s suggest BKI-1708 is predominantly cleared by CYP3A4. There was a less than 3-fold difference between BKI-1708 clearance values predicted with <i>in&nbsp;vitro</i> data and values observed in mice, rats, dogs, and non-human primates. Toxicology studies in rats and dogs demonstrated that BKI-1708 had a safety margin greater than 22. Together, these data were used to identify a safe, efficacious dosing regimen for BKI-1708 treatment of <i>Cryptosporidium</i> infection in humans. <b>