학술논문
ELQ-331 as a prototype for extremely durable chemoprotection against malaria
Document Type
article
Author
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
Source
Malaria Journal, Vol 18, Iss 1, Pp 1-17 (2019)
Subject
Language
English
ISSN
1475-2875
Abstract
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 (