Pre-erythrocytic Activity of M5717 in Monotherapy and Combination in Preclinical <i>Plasmodium</i> Infection Models

Fontinha, Diana; Arez, Francisca; Gal, Isabella Ramella; Nogueira, Gonçalo; Moita, Diana; Baeurle, Tobias Hyun Ho; Brito, Catarina; Spangenberg, Thomas; Alves, Paula M.; Prudêncio, Miguel

doi:10.1021/acsinfecdis.1c00640

Cited by 11 publications

(4 citation statements)

References 23 publications

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“…As indicated, these compounds were selected on the basis of their efficacy against ABS parasites and gametocytes as well as diversity in their evidenced drug targets and mode of action [9]. All compounds displayed efficacy against PfNF54 within expected ranges as previously reported (supplementary table S2, [13,29,[42][43][44][45]), with acceptable dose-response curves obtained (supplementary Fig. S3).…”

Section: W I T H D R a W N S E E M A N U S C R I P T D O I F O R D E ...mentioning

confidence: 99%

WITHDRAWN: Genetic complexity alters drug susceptibility of asexual and gametocyte stages ofP. falciparumto antimalarial candidates

Greyling,

van der Watt,

Gwarinda

et al. 2023

Preprint

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Malaria elimination requires interventions able to target both the asexual blood stage (ABS) parasites and transmissible gametocyte stages of Plasmodium falciparum. Lead antimalarial candidates are evaluated against clinical isolates to address key concerns regarding efficacy and confirm that the current, circulating parasites from endemic regions lacks resistance against these candidates. Whilst this has largely been performed on ABS parasites, limited data is available on the transmission-blocking efficacy of compounds with multistage activity. Here, we evaluated the efficacy of lead antimalarial candidates against both ABS parasites and late-stage gametocytes side-by-side, against clinical P. falciparum isolates from southern Africa. We additionally correlated drug efficacy to the genetic diversity of the clinical isolates as determined with a panel of well-characterized, genome spanning microsatellite (MS) markers. Our data indicate varying sensitivities of the isolates to key antimalarial candidates, both for ABS parasites and gametocyte stages. While ABS parasites were efficiently killed, irrespective of genetic complexity, antimalarial candidates lost some gametocytocidal efficacy when the gametocytes originated from genetically complex, multiple clone infections. This suggests a fitness benefit to multiclone isolates to sustain transmission and reduce drug susceptibility. In conclusion, this is the first study to investigate the efficacy of antimalarial candidates on both ABS parasites and gametocytes from P. falciparum clinical isolates where the influence of parasite genetic complexity is highlighted, ultimately aiding the malaria elimination agenda.

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Section: W I T H D R a W N S E E M A N U S C R I P T D O I F O R D E ...mentioning

confidence: 99%

WITHDRAWN: Genetic complexity alters drug susceptibility of asexual and gametocyte stages ofP. falciparumto antimalarial candidates

Greyling,

van der Watt,

Gwarinda

et al. 2023

Preprint

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show abstract

“…The results demonstrated the absence of PK interaction and an additive parasitological effect of the two compounds. Further in vitro and in vivo studies have been conducted to validate pyronaridine as a suitable partner drug for cabamiquine as a chemoprevention treatment, which supports the clinical evaluation of this novel combination therapy ( 26 ).…”

Section: Discussionmentioning

confidence: 75%

Semi-mechanistic population pharmacokinetic/pharmacodynamic modeling of a Plasmodium elongation factor 2 inhibitor cabamiquine for prevention and cure of malaria

Courlet,

Wilkins,

Oeuvray

et al. 2023

Antimicrob Agents Chemother

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Cabamiquine is a novel antimalarial agent that demonstrates the potential for chemoprevention and treatment of malaria. In this article, the dose–exposure–response relationship of cabamiquine was characterized using a population pharmacokinetic (PK)/pharmacodynamic (PD) model, incorporating the effects of cabamiquine on parasite dynamics at the liver and blood stages of malaria infection. Modeling was performed sequentially. First, a three-compartmental population PK model was developed, comprising linear elimination, a transit absorption model in combination with first-order absorption, and a recirculation model. Second, this model was expanded into a PK/PD model using parasitemia data from an induced blood stage malaria (IBSM) human challenge model. To describe the parasite growth and killing in the blood, a turnover model was used. Finally, the liver stage parasite dynamics were characterized using data from a sporozoite challenge model (SpzCh), and system parameters were fixed based on biological plausibility. Cabamiquine concentration in the central compartment was used to drive parasite killing at the blood and liver stages. Blood stage minimum inhibitory concentrations (MIC b ) were estimated at 7.12 ng/mL [95% confidence interval (CI 95% ): 6.26–7.88 ng/mL] and 1.28 ng/mL (CI 95% : 1.12–1.43 ng/mL) for IBSM and SpzCh populations, respectively, while liver stage MIC l was lower (0.61 ng/mL; CI 95% : 0.24–0.96 ng/mL). In conclusion, a population PK/PD model was developed by incorporating parasite dynamics and drug activity at the blood and liver stages based on clinical data and biological knowledge. This model can potentially facilitate antimalarial agent development by supporting the efficient selection of the optimal dosing regimen.

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“…PfeEF2 mediates the translocation of the ribosome along mRNA. M5717, a quinolone-4-carboxamide, targets PfeEF2 in multiple life cycle stages ( 29 – 31 ). Ugandan isolates were highly susceptible to M5717 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline

et al. 2023

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Pre-erythrocytic Activity of M5717 in Monotherapy and Combination in Preclinical Plasmodium Infection Models

Cited by 11 publications

References 23 publications

WITHDRAWN: Genetic complexity alters drug susceptibility of asexual and gametocyte stages ofP. falciparumto antimalarial candidates

WITHDRAWN: Genetic complexity alters drug susceptibility of asexual and gametocyte stages ofP. falciparumto antimalarial candidates

Semi-mechanistic population pharmacokinetic/pharmacodynamic modeling of a Plasmodium elongation factor 2 inhibitor cabamiquine for prevention and cure of malaria

Susceptibility of Ugandan Plasmodium falciparum Isolates to the Antimalarial Drug Pipeline

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