ELQ-331 as a prototype for extremely durable chemoprotection against malaria

• Published in: Malaria Journal
• Main Authors: Martin J. Smilkstein, Sovitj Pou, Alina Krollenbrock, Lisa A. Bleyle, Rozalia A. Dodean, Lisa Frueh, David J. Hinrichs, Yuexin Li, Thomas Martinson, Myrna Y. Munar, Rolf W. Winter, Igor Bruzual, Samantha Whiteside, Aaron Nilsen, Dennis R. Koop, Jane X. Kelly, Stefan H. I. Kappe, Brandon K. Wilder, Michael K. Riscoe
• Format: Article in Journal/Newspaper
• Language: English
• Published: BMC 2019
• Subjects: Malaria; Plasmodium; Chemoprotection; Chemoprevention; Prophylaxis; Intra-muscular; Arctic medicine. Tropical medicine; RC955-962; Infectious and parasitic diseases; RC109-216; Arctic
• Online Access: https://doi.org/10.1186/s12936-019-2921-9; https://doaj.org/article/630a94e7fc5a4c469f0ed0eacdad2650

Abstract Background The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice. Methods Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P. yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 h to 5½ months after injection. Results A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 h) and sustained (4–5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration versus time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 ...