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.

Autor:	Gaur AH; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA. Electronic address: aditya.gaur@stjude.org., McCarthy JS; Department of Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia., Panetta JC; Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA., Dallas RH; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA., Woodford J; Department of Clinical Tropical Medicine, QIMR Berghofer Medical Research Institute, Herston, QLD, Australia., Tang L; Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN, USA., Smith AM; University of Tennessee Health Science Center, University of Tennessee, Memphis, TN, USA., Stewart TB; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA., Branum KC; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA., Freeman BB 3rd; Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA., Patel ND; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA., John E; Ejohn Consulting, Richland, WA, USA., Chalon S; Medicines for Malaria Venture, Geneva, Switzerland., Ost S; University of Tennessee Health Science Center, University of Tennessee, Memphis, TN, USA., Heine RN; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA., Richardson JL; Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA., Christensen R; Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN, USA., Flynn PM; Department of Infectious Diseases, St Jude Children's Research Hospital, Memphis, TN, USA., Van Gessel Y; Eisai, Cambridge, MA, USA., Mitasev B; Eisai, Cambridge, MA, USA., Möhrle JJ; Medicines for Malaria Venture, Geneva, Switzerland., Gusovsky F; Eisai, Cambridge, MA, USA., Bebrevska L; Medicines for Malaria Venture, Geneva, Switzerland., Guy RK; University of Kentucky College of Pharmacy, University of Kentucky, Lexington, KY, USA.
Jazyk:	angličtina
Zdroj:	The Lancet. Infectious diseases [Lancet Infect Dis] 2020 Aug; Vol. 20 (8), pp. 964-975. Date of Electronic Publication: 2020 Apr 08.
DOI:	10.1016/S1473-3099(19)30611-5
Abstrakt:	Background: (+)-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. Methods: 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 (PRR 48 ) 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. Both studies are registered with ClinicalTrials.gov (NCT02661373 for the phase 1a and NCT02867059 for the phase 1b). Findings: In the phase 1a, 23 healthy participants were enrolled and received one to three non-consecutive doses of SJ733 between March 14 and Dec 7, 2016. SJ733 was safe and well tolerated at all doses and in fasted and fed conditions. 119 adverse events were recorded: 54 (45%) were unrelated, 63 (53%) unlikely to be related, and two (2%) possibly related to SJ733. In the phase 1b, 17 malaria-naive, healthy participants were enrolled. Seven participants in the 150 mg dose cohort were inoculated and dosed with SJ733. Eight participants in the 600 mg dose cohort were inoculated, but two participants could not be dosed with SJ733. Two additional participants were subsequently inoculated and dosed with SJ733. SJ733 exposure increased proportional to the dose through to the 600 mg dose, then was saturable at higher doses. Fasted participants receiving 600 mg exceeded the target area under the concentration curve extrapolated to infinity (AUC 0-∞ ) of 13 000 μg × h/L (median AUC 0-∞ 24 283 [IQR 16 135-31 311] μg × h/L, median terminal half-life 17·4 h [IQR 16·1-24·0], and median timepoint at which peak plasma concentration is reached 1·0 h [0·6-1·3]), and this dose was tested in the phase 1b. All 15 participants dosed with SJ733 had at least one adverse event. Of the 172 adverse events recorded, 128 (74%) were mild. The only adverse event attributed to SJ733 was mild bilateral foot paraesthesia that lasted 3·75 h and resolved spontaneously. The most common adverse events were related to malaria. Based on parasite clearance half-life, the derived log 10 PRR 48 and corresponding parasite clearance half-lives were 2·2 (95% CI 2·0-2·5) and 6·47 h (95% CI 5·88-7·18) for 150 mg, and 4·1 (3·7-4·4) and 3·56 h (3·29-3·88) for 600 mg. Interpretation: The favourable pharmacokinetic, tolerability, and safety profile of SJ733, and rapid antiparasitic effect support its development as a fast-acting component of combination antimalarial therapy. Funding: Global Health Innovative Technology Fund, Medicines for Malaria Venture, and the American Lebanese Syrian Associated Charities. (Copyright © 2020 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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