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J Infect Dis. 2017 Jul 1;216(1):55-63. doi: 10.1093/infdis/jix247.

Necessity of Bumped Kinase Inhibitor Gastrointestinal Exposure in Treating Cryptosporidium Infection.

Author information

1
Department of Medicine, Division of Allergy and Infectious Disease, Center for Emerging and Reemerging Infectious Disease.
2
School of Animal and Comparative Biomedical Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson.
3
Center for Tropical and Emerging Global Diseases.
4
Department of Chemistry.
5
Department of Biochemistry, Biomolecular Structure Center, University of Washington, Seattle.
6
Department of Biochemistry.
7
Department of Cellular Biology, University of Georgia, Athens.

Abstract

There is a substantial need for novel therapeutics to combat the widespread impact caused by Crytosporidium infection. However, there is a lack of knowledge as to which drug pharmacokinetic (PK) characteristics are key to generate an in vivo response, specifically whether systemic drug exposure is crucial for in vivo efficacy. To identify which PK properties are correlated with in vivo efficacy, we generated physiologically based PK models to simulate systemic and gastrointestinal drug concentrations for a series of bumped kinase inhibitors (BKIs) that have nearly identical in vitro potency against Cryptosporidium but display divergent PK properties. When BKI concentrations were used to predict in vivo efficacy with a neonatal model of Cryptosporidium infection, these concentrations in the large intestine were the sole predictors of the observed in vivo efficacy. The significance of large intestinal BKI exposure for predicting in vivo efficacy was further supported with an adult mouse model of Cryptosporidium infection. This study suggests that drug exposure in the large intestine is essential for generating a superior in vivo response, and that physiologically based PK models can assist in the prioritization of leading preclinical drug candidates for in vivo testing.

KEYWORDS:

Cryptosporidium; drug development; gastrointestinal; physiologically based pharmacokinetic model

PMID:
28541457
PMCID:
PMC5853285
DOI:
10.1093/infdis/jix247
[Indexed for MEDLINE]
Free PMC Article

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