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 Koop, Jane X. Kelly, Stefan H.I. Kappe, Brandon K. Wilder, Michael Riscoe

Research output: Contribution to journalArticle

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

Fingerprint

Malaria
Prodrugs
Plasmodium yoelii
Pharmacokinetics
Sporozoites
Injections
6-Chloro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one
Sesame Oil
Benzyl Alcohol
Intramuscular Injections
Antimalarials
Electron Transport
Luciferases
Parasites

Keywords

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

ASJC Scopus subject areas

  • Parasitology
  • Infectious Diseases

Cite this

Smilkstein, M. J., Pou, S., Krollenbrock, A., Bleyle, L. A., Dodean, R. A., Frueh, L., ... Riscoe, M. (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

ELQ-331 as a prototype for extremely durable chemoprotection against malaria. / 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; Kelly, Jane X.; Kappe, Stefan H.I.; Wilder, Brandon K.; Riscoe, Michael.

In: Malaria Journal, Vol. 18, No. 1, 291, 27.08.2019.

Research output: Contribution to journalArticle

Smilkstein, MJ, Pou, S, Krollenbrock, A, Bleyle, LA, Dodean, RA, Frueh, L, Hinrichs, DJ, Li, Y, Martinson, T, Munar, MY, Winter, RW, Bruzual, I, Whiteside, S, Nilsen, A, Koop, D, Kelly, JX, Kappe, SHI, Wilder, BK & Riscoe, M 2019, 'ELQ-331 as a prototype for extremely durable chemoprotection against malaria', Malaria Journal, vol. 18, no. 1, 291. https://doi.org/10.1186/s12936-019-2921-9
Smilkstein MJ, Pou S, Krollenbrock A, Bleyle LA, Dodean RA, Frueh L et al. ELQ-331 as a prototype for extremely durable chemoprotection against malaria. Malaria Journal. 2019 Aug 27;18(1). 291. https://doi.org/10.1186/s12936-019-2921-9
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 ; Kelly, Jane X. ; Kappe, Stefan H.I. ; Wilder, Brandon K. ; Riscoe, Michael. / ELQ-331 as a prototype for extremely durable chemoprotection against malaria. In: Malaria Journal. 2019 ; Vol. 18, No. 1.
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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.",
keywords = "Chemoprevention, Chemoprotection, Intra-muscular, Long-acting, Malaria, Plasmodium, Prodrug, Prophylaxis",
author = "Smilkstein, {Martin J.} and Sovitj Pou and Alina Krollenbrock and Bleyle, {Lisa A.} and Dodean, {Rozalia A.} and Lisa Frueh and Hinrichs, {David J.} and Yuexin Li and Thomas Martinson and Munar, {Myrna Y.} and Winter, {Rolf W.} and Igor Bruzual and Samantha Whiteside and Aaron Nilsen and Dennis Koop and Kelly, {Jane X.} and Kappe, {Stefan H.I.} and Wilder, {Brandon K.} and Michael Riscoe",
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TY - JOUR

T1 - ELQ-331 as a prototype for extremely durable chemoprotection against malaria

AU - Smilkstein, Martin J.

AU - Pou, Sovitj

AU - Krollenbrock, Alina

AU - Bleyle, Lisa A.

AU - Dodean, Rozalia A.

AU - Frueh, Lisa

AU - Hinrichs, David J.

AU - Li, Yuexin

AU - Martinson, Thomas

AU - Munar, Myrna Y.

AU - Winter, Rolf W.

AU - Bruzual, Igor

AU - Whiteside, Samantha

AU - Nilsen, Aaron

AU - Koop, Dennis

AU - Kelly, Jane X.

AU - Kappe, Stefan H.I.

AU - Wilder, Brandon K.

AU - Riscoe, Michael

PY - 2019/8/27

Y1 - 2019/8/27

N2 - 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.

AB - 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.

KW - Chemoprevention

KW - Chemoprotection

KW - Intra-muscular

KW - Long-acting

KW - Malaria

KW - Plasmodium

KW - Prodrug

KW - Prophylaxis

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