+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers



Efficacy of OZ439 (artefenomel) against early Plasmodium falciparum blood-stage malaria infection in healthy volunteers



Journal of Antimicrobial ChemoTherapy 71(9): 2620-2627



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.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 057739420

Download citation: RISBibTeXText

PMID: 27272721

DOI: 10.1093/jac/dkw174


Related references

Antimalarial activity of artefenomel (OZ439), a novel synthetic antimalarial endoperoxide, in patients with Plasmodium falciparum and Plasmodium vivax malaria: an open-label phase 2 trial. Lancet. Infectious Diseases 16(1): 61-69, 2016

A Phase II pilot trial to evaluate safety and efficacy of ferroquine against early Plasmodium falciparum in an induced blood-stage malaria infection study. Malaria Journal 15: 469, 2017

Low-level Plasmodium falciparum blood-stage infection causes dendritic cell apoptosis and dysfunction in healthy volunteers. Journal of Infectious Diseases 206(3): 333-340, 2012

Demonstration of the Blood-Stage Plasmodium falciparum Controlled Human Malaria Infection Model to Assess Efficacy of the P. falciparum Apical Membrane Antigen 1 Vaccine, FMP2.1/AS01. Journal of Infectious Diseases 213(11): 1743-1751, 2017

A pilot randomised trial of induced blood-stage Plasmodium falciparum infections in healthy volunteers for testing efficacy of new antimalarial drugs. Plos One 6(8): E21914, 2012

T lymphocytes from volunteers immunized with irradiated Plasmodium falciparum sporozoites recognize liver and blood stage malaria antigens. Journal of Immunology 155(8): 4072-4077, 1995

Density-dependent blood stage Plasmodium falciparum suppresses malaria super-infection in a malaria holoendemic population. American Journal of Tropical Medicine and Hygiene 89(5): 850-856, 2013

A randomised, double-blind clinical phase II trial of the efficacy, safety, tolerability and pharmacokinetics of a single dose combination treatment with artefenomel and piperaquine in adults and children with uncomplicated Plasmodium falciparum malaria. Bmc Medicine 15(1): 181, 2018

Challenges of assessing the clinical efficacy of asexual blood-stage Plasmodium falciparum malaria vaccines. Human Vaccines and Immunotherapeutics 9(9): 1831-1840, 2014

Development of cultured Plasmodium falciparum blood-stage malaria cell banks for early phase in vivo clinical trial assessment of anti-malaria drugs and vaccines. Malaria Journal 14: 143, 2016

Experimentally induced blood-stage Plasmodium vivax infection in healthy volunteers. Journal of Infectious Diseases 208(10): 1688-1694, 2013

Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria. Molecular Pharmaceutics 2019, 2019

Vaccination with chemically attenuated Plasmodium falciparum asexual blood-stage parasites induces parasite-specific cellular immune responses in malaria-naïve volunteers: a pilot study. Bmc Medicine 16(1): 184, 2018

Controlled human malaria infection of healthy lifelong malaria-exposed adults to assess safety, immunogenicity and efficacy of the asexual blood stage malaria vaccine candidate GMZ2. Clinical Infectious Diseases 2018, 2018

Early Changes in CD4+ T-Cell Activation During Blood-Stage Plasmodium falciparum Infection. Journal of Infectious Diseases 218(7): 1119-1129, 2018