Malaria journal · 2022
Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside.
СтатьяНазвание и аннотация: Перевод в очереди
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Khandelwal Akash, Arez Francisca, Alves Paula M, Badolo Lassina, Brito Catarina, Fischli Christoph, Fontinha Diana, Oeuvray Claude, Prudêncio Miguel, Rottmann Matthias, Wilkins Justin, Yalkinoglu Özkan, Bagchus Wilhelmina M, Spangenberg Thomas
Аннотация
BACKGROUND: Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality.
METHODS: M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study.
RESULTS: Doses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively.
CONCLUSIONS: This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.
METHODS: M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study.
RESULTS: Doses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively.
CONCLUSIONS: This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.