Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers.
OZ439, or artefenomel, is an investigational synthetic ozonide antimalarial with similar potency, but a significantly improved pharmacokinetic profile, compared with artemisinins. We wished to measure key pharmacokinetic and pharmacodynamic parameters and the pharmacokinetic/pharmacodynamic relationship of artefenomel in humans to guide the drug's further development as combination therapy in patients.



We tested artefenomel in the human induced blood-stage malaria (IBSM) model. Plasmodium infection was monitored by quantitative PCR (qPCR) and upon reaching 1000 parasites/mL single doses of 100, 200 and 500 mg of artefenomel were administered orally with evaluation of drug exposure and parasitaemia until rescue treatment after 16 days or earlier, if required.



A single 100 mg dose had only a transient effect, while the 200 mg dose resulted in a significant reduction in parasitaemia before early recrudescence. At the highest (500 mg) dose, initial clearance of parasites below the limit of detection of qPCR was observed, with a 48 h parasite reduction ratio (PRR48) >10 000 and a parasite clearance half-life of 3.6 h (95% CI 3.4-3.8 h). However, at this dose, recrudescence was seen in four of eight subjects 6-10 days after treatment. Pharmacokinetic/pharmacodynamic modelling predicted an MIC of 4.1 ng/mL.



These results confirm the antimalarial potential of artefenomel for use in a single-exposure combination therapy. The observations from this study support and will assist further clinical development of artefenomel.
QIMR Berghofer Medical Research Institute, 300 Herston Rd, Brisbane, QLD 4006, Australia University of Queensland, Brisbane, St Lucia, QLD 4006, Australia.
James S
JS
McCarthy
Department of Translational Medicine, Medicines for Malaria Venture, Route de Pré-Bois 20, 1215 Meyrin, Geneva, Switzerland.
Mark
M
Baker
QIMR Berghofer Medical Research Institute, 300 Herston Rd, Brisbane, QLD 4006, Australia.
Peter
P
O'Rourke
QIMR Berghofer Medical Research Institute, 300 Herston Rd, Brisbane, QLD 4006, Australia.
Louise
L
Marquart
QIMR Berghofer Medical Research Institute, 300 Herston Rd, Brisbane, QLD 4006, Australia University of Queensland, Brisbane, St Lucia, QLD 4006, Australia QPharm Pty Ltd, Brisbane, 300 Herston Rd, Herston, QLD 4006, Australia Mater Health Services, Raymond Terrace, South Brisbane, QLD 4101, Australia.
Paul
P
Griffin
Department of Translational Medicine, Medicines for Malaria Venture, Route de Pré-Bois 20, 1215 Meyrin, Geneva, Switzerland.
Rob
R
Hooft van Huijsduijnen
Department of Translational Medicine, Medicines for Malaria Venture, Route de Pré-Bois 20, 1215 Meyrin, Geneva, Switzerland moehrlej@mmv.org.
Jörg J
JJ
Möhrle
D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015331:Cohort Studies; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008826:Microbial Sensitivity Tests; D059208:Parasite Load; D010545:Peroxides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D016896:Treatment Outcome; D055815:Young Adult
D000962:Antimalarials; D010545:Peroxides; D000218:Adamantane; C558165:artefenomel