Pharmacokinetic analysis of bumped-kinase inhibitors in horses demonstrates their potential utility for prevention and treatment of equine protozoal myeloencephalitis.

Overview

• This research investigates the pharmacokinetics of bumped-kinase inhibitors (BKIs) in horses to evaluate their potential for preventing and treating equine protozoal myeloencephalitis (EPM).
• The study identifies BKI-1708 as a promising candidate based on its effectiveness against the protozoa Sarcocystis neurona, its safety profile, systemic distribution, and potential for clinical use despite limited central nervous system (CNS) penetration.

Research Objectives

• To assess the systemic and central nervous system (CNS) distribution of BKIs in healthy horses.
• To monitor for any potential side effects from BKI administration.
• To identify a lead compound suitable for clinical trials aimed at treating or preventing EPM.

Background on Equine Protozoal Myeloencephalitis (EPM)

• EPM is a neurological disease in horses caused mainly by the protozoan parasite Sarcocystis neurona.
• Treatment options are limited by drug efficacy, CNS penetration, and safety.
• Bumped-kinase inhibitors target apicomplexan kinases, potentially inhibiting the growth of protozoan parasites.

Methodology

• Conducted nine pharmacokinetic experiments between March 2021 and November 2024 in healthy horses.
• Screened three BKI compounds—1708, 1748, and 1841—using:
  • In vitro growth assays on Sarcocystis neurona to measure inhibitory effects.
  • Intravenous (IV) pharmacokinetic studies to assess systemic drug behavior.
• Selected BKI-1708 as a lead compound for more detailed investigation involving:
  • Single-dose oral administration.
  • Multiday oral administration.
• Collected serial plasma samples to monitor systemic distribution over time.
• Measured drug concentrations in cerebrospinal fluid (CSF) and nervous tissue to evaluate CNS penetration.
• Performed daily physical exams and blood testing (CBC, biochemistry) to track side effects.

Key Findings

• In vitro efficacy: BKI-1708 inhibited S. neurona growth at low nanomolar concentrations, with an IC50 of approximately 42 nM.
• Pharmacokinetics:
  • After IV and oral administration, BKI-1708 achieved therapeutic plasma concentrations, with average peak plasma concentration around 5 μM.
  • Half-life in plasma was about 25 hours at steady state, indicating sustained systemic presence.
  • Single daily dosing was sufficient to maintain therapeutic levels systemically.
• CNS penetration:
  • BKI-1708 concentrations in CSF and nervous tissue were found to be approximately 25 times lower than plasma levels.
  • This suggests limited ability of BKI-1708 to cross the blood-brain barrier and accumulate in the CNS.
• Safety: No adverse side effects were observed during the study period based on physical exams and blood evaluations.

Conclusions and Implications

• BKI-1708 shows promising systemic pharmacokinetic properties and in vitro efficacy against S. neurona, making it a strong candidate for further evaluation.
• Despite limited CNS penetration, which may reduce its effectiveness against established CNS infections, BKI-1708 could still be useful as a prophylactic drug preventing EPM by controlling parasite presence systemically before CNS invasion.
• BKI-1708 may also have broader applications for systemic apicomplexan diseases in horses, including infections like piroplasmosis.
• Future studies could investigate intermittent dosing protocols for prophylaxis and combination therapies to improve CNS drug delivery.
• Clinical trials on horses with confirmed EPM are warranted to confirm therapeutic potential and optimize treatment regimens.