Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development

Aditya H Gaur, John C Panetta, Amber M Smith, Ronald H Dallas, Burgess B Freeman, Tracy B Stewart, Li Tang, Elizabeth John, Kristen C Branum, Nehali D Patel, Shelley Ost, Ryan N Heine, Julie L Richardson, Jared T Hammill, Lidiya Bebrevska, Fabian Gusovsky, Noritsugu Maki, Toshiharu Yanagi, Patricia M Flynn, James S McCarthyStephan Chalon, R Kiplin Guy

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: SJ733, a newly developed inhibitor of P. falciparum ATP4, has a favorable safety profile and rapid antiparasitic effect but insufficient duration to deliver a single-dose cure of malaria. We investigated the safety, tolerability, and pharmacokinetics of a multidose SJ733 regimen and a single-dose pharmacoboost approach using cobicistat to inhibit CYP3A4, thereby increasing exposure.

METHODS: Two multidose unboosted cohorts (n = 9) (SJ733, 300 mg and 600 mg daily for 3 days) followed by three single-dose boosted cohorts combining SJ733 (n = 18) (75-, 300-, or 600-mg single dose) with cobicistat (150-mg single dose) as a pharmacokinetic booster were evaluated in healthy volunteers (ClinicalTrials.gov: NCT02661373).

FINDINGS: All participants tolerated SJ733 well, with no serious adverse events (AEs), dose-limiting toxicity, or clinically significant electrocardiogram or laboratory test findings. All reported AEs were Grade 1, clinically insignificant, and considered unlikely or unrelated to SJ733. Compared to unboosted cohorts, the SJ733/cobicistat-boosted cohorts showed a median increase in area under the curve and maximum concentration of 3·9 × and 2·6 ×, respectively, and a median decrease in the ratio of the major CYP3A-produced metabolite SJ506 to parent drug of 4·6 × . Incorporating these data in a model of parasite dynamics indicated that a 3-day regimen of SJ733/cobicistat (600 mg/150 mg daily) relative to a single 600-mg dose ± cobicistat would increase parasite clearance from 10 6 to 10 12 parasites/µL.

INTERPRETATION: The multidose and pharmacoboosted approaches to delivering SJ733 were well-tolerated and significantly increased drug exposure and prediction of cure. This study supports the further development of SJ733 and demonstrates an innovative pharmacoboost approach for an antimalarial.

FUNDING: Global Health Innovative Technology Fund, Medicines for Malaria Venture, National Institutes of Health, and American Lebanese Syrian Associated Charities.

Original languageEnglish
Pages (from-to)104065
JournalEBioMedicine
Volume80
DOIs
StatePublished - Jun 2022

Bibliographical note

Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

Keywords

  • Antimalarials/adverse effects
  • Cobicistat/therapeutic use
  • Folic Acid Antagonists
  • Heterocyclic Compounds, 4 or More Rings
  • Humans
  • Isoquinolines
  • Malaria/drug therapy
  • Malaria, Falciparum/drug therapy
  • Plasmodium falciparum

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