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

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

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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 5 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 4 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 concentration is sustained above a minimum fully-protective threshold (60-80 nM). Conclusions: Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.

Original languageEnglish (US)
Article number291
JournalMalaria Journal
Volume18
Issue number1
DOIs
StatePublished - Aug 27 2019

Keywords

  • Chemoprevention
  • Chemoprotection
  • Intra-muscular
  • Long-acting
  • Malaria
  • Plasmodium
  • Prodrug
  • Prophylaxis

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

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    Smilkstein, M. J., Pou, S., Krollenbrock, A., Bleyle, L. A., Dodean, R. A., Frueh, L., Hinrichs, D. J., Li, Y., Martinson, T., Munar, M. Y., Winter, R. W., Bruzual, I., Whiteside, S., Nilsen, A., Koop, D. R., Kelly, J. X., Kappe, S. H. I., Wilder, B. K., & Riscoe, M. K. (2019). ELQ-331 as a prototype for extremely durable chemoprotection against malaria. Malaria Journal, 18(1), [291]. https://doi.org/10.1186/s12936-019-2921-9