Bumped Kinase Inhibitor for Toxoplasmosis and and Sarcocystosis

The research conducted at the University of Kentucky will include experiments described in Aim 1b of the proposal. Specifically, my lab will perform in vitro growth assays in year 1 to confirm that new lead BKIs are effective at inhibiting S. neurona propagation in cell culture, as observed with the BKIs previously tested. The primary focus of our research, however, are outlined in Aim 3 of the project narrative. We will conduct two pharmacokinetic experiments in horses fitted with indwelling, subarachnoidal catheters to allow repeated collection of cerebrospinal fluid. Initially, we will conduct a single-dose PK study of two lead BKIs using 6 horses (N = 3/group) to assess plasma and CSF maximum concentrations and clearance of the compounds after oral dosing. Based on these findings, we will then conduct a multiple-dose experiment in 6 horses over a 5-day period to determine time to steady state and maximum peak and trough concentrations of the BKIs in plasma and CSF. The PK experiments will be conducted in years 1 and 2 of the project. Finally, we will perform a non-inferiority trial in naturally-infected EPM horses comparing the treatment efficacy of the lead BKI with the current favored anti-protozoal treatment for EPM, ponazuril (Marquis®). In collaboration with Dr. Reed, 60 horses diagnosed with EPM will be enrolled in the study and assigned randomly to either the BKI treatment group or the ponazuril treatment group. Horses will be monitored for improvement in neurologic grade and decline in CSF antibody titers to assess treatment efficacy. The treatment trial will initiate in year 3 and continue through year 5 of the project.