Establishing Anti-Cryptosporidial Drug Pharmacokinetic/Pharmacodynamic Relationships

Samuel Arnold of the University of Washington in the U.S. will develop methods to evaluate drug candidates for treating Cryptosporidium infections, which cause severe diarrhea particularly in young children from developing countries. There are no effective drugs against the Cryptosporidium parasite. This is partly because when it infects humans it becomes isolated in specific cells lining the gastrointestinal tract, which is where a drug would also need to be located at sufficient concentrations to be effective. However, the standard in vitro models are unable to easily and rapidly predict the efficacy of multiple drug candidates at this specific location. To address this, they will build a cell model of the intestinal wall that can also be infected with Cryptosporidium, and measure the permeability of a panel of protein kinase inhibitors that they have developed to kill the parasites. They will also use the software platform Gastroplus that can simulate the behavior of a drug once it has been administered and predict concentrations at multiple sites in the gastrointestinal tract. They will evaluate their method for predicting drug activity in vivo by testing the drugs in a neonatal mouse model of Cryptosporidium infection.