Safety, tolerability, pharmacokinetics, and antimalarial efficacy of a novel Plasmodium falciparum ATP4 inhibitor SJ733: a first-in-human and induced blood-stage malaria phase 1a/b trial

(+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. The phase 1a was a singl...

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Published in:The Lancet infectious diseases 2020-08, Vol.20 (8), p.964-975
Main Authors: Gaur, Aditya H, McCarthy, James S, Panetta, John C, Dallas, Ronald H, Woodford, John, Tang, Li, Smith, Amber M, Stewart, Tracy B, Branum, Kristen C, Freeman, Burgess B, Patel, Nehali D, John, Elizabeth, Chalon, Stephan, Ost, Shelley, Heine, Ryan N, Richardson, Julie L, Christensen, Robbin, Flynn, Patricia M, Van Gessel, Yvonne, Mitasev, Branko, Möhrle, Jörg J, Gusovsky, Fabian, Bebrevska, Lidiya, Guy, R Kiplin
Format: Article
Language:English
Subjects:
Anemia
Antimalarial activity
Antimalarial agents
Antiparasitic agents
Bioavailability
Blood
Charities
Dosage
Drug dosages
Drug resistance
Erythrocytes
Exposure
FDA approval
Global health
Half-life
Infections
Infectious diseases
Inhibitors
Inoculation
Malaria
Novels
Oral administration
Parasites
Pharmacodynamics
Pharmacokinetics
Pharmacology
Plasmodium falciparum
Research facilities
Safety
Studies
Vector-borne diseases
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Summary:(+)-SJ000557733 (SJ733) is a novel, orally bioavailable inhibitor of Plasmodium falciparum ATP4. In this first-in-human and induced blood-stage malaria phase 1a/b trial, we investigated the safety, tolerability, pharmacokinetics, and antimalarial activity of SJ733 in humans. The phase 1a was a single-centre, dose-escalation, first-in-human study of SJ733 allowing modifications to dose increments and dose-cohort size on the basis of safety and pharmacokinetic results. The phase 1a took place at St Jude Children's Research Hospital and at the University of Tennessee Clinical Research Center (Memphis, TN, USA). Enrolment in more than one non-consecutive dose cohort was allowed with at least 14 days required between doses. Participants were fasted in seven dose cohorts and fed in one 600 mg dose cohort. Single ascending doses of SJ733 (75, 150, 300, 600, 900, or 1200 mg) were administered to participants, who were followed up for 14 days after SJ733 dosing. Phase 1a primary endpoints were safety, tolerability, and pharmacokinetics of SJ733, and identification of an SJ733 dose to test in the induced blood-stage malaria model. The phase 1b was a single-centre, open-label, volunteer infection study using the induced blood-stage malaria model in which fasted participants were intravenously infected with blood-stage P falciparum and subsequently treated with a single dose of SJ733. Phase 1b took place at Q-Pharm (Herston, QLD, Australia) and was initiated only after phase 1a showed that exposure exceeding the threshold minimum exposure could be safely achieved in humans. Participants were inoculated on day 0 with P falciparum-infected human erythrocytes (around 2800 parasites in the 150 mg dose cohort and around 2300 parasites in the 600 mg dose cohort), and parasitaemia was monitored before malaria inoculation, after inoculation, immediately before SJ733 dosing, and then post-dose. Participants were treated with SJ733 within 24 h of reaching 5000 parasites per mL or at a clinical score higher than 6. Phase 1b primary endpoints were calculation of a parasite reduction ratio (PRR48) and parasite clearance half-life, and safety and tolerability of SJ733 (incidence, severity, and drug-relatedness of adverse events). In both phases of the trial, SJ733 hydrochloride salt was formulated as a powder blend in capsules containing 75 mg or 300 mg for oral administration. Healthy men and women (of non-childbearing potential) aged 18–55 years were eligible for both studies. Bo
ISSN:1473-3099
1474-4457
DOI:10.1016/S1473-3099(19)30611-5