Advances in bumped kinase inhibitors for human and animal therapy for cryptosporidiosis

Abstract

Improvements have been made to the safety and efficacy of bumped kinase inhibitors, and they are advancing toward human and animal use for treatment of cryptosporidiosis. As the understanding of bumped kinase inhibitor pharmacodynamics for cryptosporidiosis therapy has increased, it has become clear that better compounds for efficacy do not necessarily require substantial systemic exposure. We now have a bumped kinase inhibitor with reduced systemic exposure, acceptable safety parameters, and efficacy in both the mouse and newborn calf models of cryptosporidiosis. Potential cardiotoxicity is the limiting safety parameter to monitor for this bumped kinase inhibitor. This compound is a promising pre-clinical lead for cryptosporidiosis therapy in animals and humans.

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice

“…Recently BKI-1294 treatment was applied in pregnant sheep experimentally infected with T. gondii oocysts where it was partially efficacious against T. gondii infection, and no adverse effects of drug treatment were noted in this small ruminant model [36]. BKI-1369 and BKI-1770 are lead compounds for the treatment of diarrhea caused by cryptosporidiosis in calves [15,17]. In addition, excellent BKI-1369 efficacy was demonstrated against Cystisospora suis infection in piglets [18], and in a pig model of acute diarrhea caused by Cryptosporidium hominis ([16].…”

Therapeutic Efficacy of Bumped Kinase Inhibitor 1369 in a Pig Model of Acute Diarrhea Caused by Cryptosporidium hominis

“…In the present study, we used the GB piglet model to evaluate the efficacy of BKI 1369, a candidate with less potential cardiotoxicity than that of BKI 1294, using the well-characterized C. hominis strain TU502 (12). BKI 1369 has been well characterized for potency, stability, metabolism, toxicity, and pharmacokinetics and has been shown to be potent against C. parvum in infected mice and calves (13). Piglets treated with BKI 1369 exhibited a significant reduction of oocyst excretion in feces, with considerable symptomatic improvement.…”

Calf Clinical Model of Cryptosporidiosis for Efficacy Evaluation of Therapeutics

“…In a calf model similar to the preceding, paromomycin demonstrated prophylactic efficacy against C. parvum challenge and proof of concept, but the drug dosage required was determined to be cost prohibitive for veterinary use [16]. While there is no universally applicable design for the calf model given geographic, institutional, and laboratory constraints, we have used the acute model described here to consistently replicate data demonstrating therapeutic efficacy for multiple bumped kinase inhibitor (BKI) drugs for further study, as well as to consistently replicate data demonstrating lower, clinically less satisfactory efficacy for other BKIs to eliminate from further study [11,17] (M.W. Riggs and D.A.…”

“…Reduction of oocyst shedding is an important treatment outcome when considering the epidemiologic importance of the environmental parasite burden and exposure risk to both humans and livestock [19]. By 8 or 9 days post infection (DPI), most untreated control calves are beginning to resolve diarrhea in this model [11,17]. Therefore, we end the experiment at 10 DPI to conclude initial efficacy determinations.…”

“…If this occurs, note in the records the estimated volume of inoculum not received and that data from the calf may not be suitable for use in final analyses. 17. It is potentially possible that some urine may enter the fecal collection bins, voiding accurate fecal volume determination.…”