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 Branum, Nehali Patel, Shelley Ost, Ryan N. Heine, Julie Richardson, Jared T. Hammill, Lidiya Bebrevska, Fabian Gusovsky, Noritsugu Maki, Toshiharu Yanagi, Patricia M. Flynn, James McCarthy, Stephan Chalon, R. Kiplin Guy
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: 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.