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

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 o...

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Veröffentlicht in:Malaria journal 2019-08, Vol.18 (1), p.291-17, Article 291
Hauptverfasser: Smilkstein, Martin J, Pou, Sovitj, Krollenbrock, Alina, Bleyle, Lisa A, Dodean, Rozalia A, Frueh, Lisa, Hinrichs, David J, Li, Yuexin, Martinson, Thomas, Munar, Myrna Y, Winter, Rolf W, Bruzual, Igor, Whiteside, Samantha, Nilsen, Aaron, Koop, Dennis R, Kelly, Jane X, Kappe, Stefan H I, Wilder, Brandon K, Riscoe, Michael K
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Sprache:eng
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Zusammenfassung: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. 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. 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 (
ISSN:1475-2875
1475-2875
DOI:10.1186/s12936-019-2921-9