Improved safety margin for embryotoxicity in rats for the new endoperoxide artefenomel (OZ439) as compared to artesunate

Background Combination medicines including an artemisinin are the mainstay of antimalarial therapy. Artemisinins are potent embryotoxicants in animal species due to their trioxane moiety. Methods As part of its development, the new synthetic trioxolane antimalarial artefenomel (OZ439) was tested in...

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Bibliographic Details
Published in:Birth defects research 2018-04, Vol.110 (7), p.553-578
Main Authors: Clark, Robert L., Edwards, Tammye L., Longo, Monica, Kinney, Joseph, Walker, Don K., Rhodes, Jon, Clode, Sally A., Rückle, Thomas, Wells, Timothy, Andenmatten, Nicole, Huber, Anna Christine
Format: Article
Language:English
Subjects:
Adamantane - analogs & derivatives
Adamantane - pharmacokinetics
Adamantane - toxicity
Animals
Antimalarials - toxicity
Artefenomel
Artemisinins - toxicity
artesunate
Artesunate - toxicity
Benzoxazines - toxicity
Dose-Response Relationship, Drug
embryo
Embryo, Mammalian - drug effects
embryotoxicity
Female
Fetal Development - drug effects
Gestational Age
Heme - biosynthesis
Organ Culture Techniques
Organogenesis - drug effects
Peroxides - pharmacokinetics
Peroxides - toxicity
Phthalimides - toxicity
rat
Rats
safety margin
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Summary:Background Combination medicines including an artemisinin are the mainstay of antimalarial therapy. Artemisinins are potent embryotoxicants in animal species due to their trioxane moiety. Methods As part of its development, the new synthetic trioxolane antimalarial artefenomel (OZ439) was tested in rat whole embryo culture and in rat embryo‐fetal toxicity studies with dosing throughout organogenesis or with a single dose on Gestational Day (GD) 12. The single‐dose studies included groups treated with artesunate to allow a direct comparison of the embryotoxicity of the two antimalarials and included toxicokinetics hematology and histological examination of embryos. In addition, the distribution of artefenomel‐related material in plasma was determined after the administration of 14C‐artefenomel. Results Artefenomel and artesunate showed similar patterns of embryotoxicity including cardiovascular defects and resorption with a steep dose‐response. They both also caused a depletion of circulating embryonic erythroblasts both in vitro and in vivo and decreases in maternal reticulocyte count. However, artefenomel was ∼250‐fold less potent than the active metabolite of artesunate (dihydroartemisinin) as an embryotoxicant in vitro. The safety margin (based on AUC) for artefenomel administered on GD 12 was approximately 100‐fold greater than that for artesunate. Also, unlike artesunate, artefenomel was not a selective developmental toxicant. Conclusions The lesser embryotoxicity of artefenomel is likely linked to its original design which included two blocking side groups that had been introduced to lower the reactivity with ferrous iron. Our data support the hypothesis that artefenomel's improved safety margin is linked to a lower potential for inhibiting heme biosynthesis in embryonic erythroblasts.
ISSN:2472-1727
2472-1727
DOI:10.1002/bdr2.1170