PMID- 35598441
OWN - NLM
STAT- MEDLINE
DCOM- 20220614
LR  - 20240214
IS  - 2352-3964 (Electronic)
IS  - 2352-3964 (Linking)
VI  - 80
DP  - 2022 Jun
TI  - Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the 
      pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug 
      development.
PG  - 104065
LID - S2352-3964(22)00246-8 [pii]
LID - 10.1016/j.ebiom.2022.104065 [doi]
LID - 104065
AB  - 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 x and 
      2.6 x, respectively, and a median decrease in the ratio of the major 
      CYP3A-produced metabolite SJ506 to parent drug of 4.6 x . 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/microL. 
      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.
CI  - Copyright (c) 2022 The Authors. Published by Elsevier B.V. All rights reserved.
FAU - Gaur, Aditya H
AU  - Gaur AH
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States. Electronic address: 
      aditya.gaur@stjude.org.
FAU - Panetta, John C
AU  - Panetta JC
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Smith, Amber M
AU  - Smith AM
AD  - University of Tennessee Health Science Center, Memphis, TN, United States.
FAU - Dallas, Ronald H
AU  - Dallas RH
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Freeman, Burgess B 3rd
AU  - Freeman BB 3rd
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Stewart, Tracy B
AU  - Stewart TB
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Tang, Li
AU  - Tang L
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - John, Elizabeth
AU  - John E
AD  - EJOHN Consulting, Richland, WA, United States.
FAU - Branum, Kristen C
AU  - Branum KC
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Patel, Nehali D
AU  - Patel ND
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Ost, Shelley
AU  - Ost S
AD  - University of Tennessee Health Science Center, Memphis, TN, United States.
FAU - Heine, Ryan N
AU  - Heine RN
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Richardson, Julie L
AU  - Richardson JL
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - Hammill, Jared T
AU  - Hammill JT
AD  - University of Kentucky College of Pharmacy, Lexington, KY, United States.
FAU - Bebrevska, Lidiya
AU  - Bebrevska L
AD  - Medicines for Malaria Venture, Geneva, Switzerland.
FAU - Gusovsky, Fabian
AU  - Gusovsky F
AD  - Eisai Inc., Cambridge, MA, United States.
FAU - Maki, Noritsugu
AU  - Maki N
AD  - Eisai Inc., Cambridge, MA, United States.
FAU - Yanagi, Toshiharu
AU  - Yanagi T
AD  - Eisai Inc., Cambridge, MA, United States.
FAU - Flynn, Patricia M
AU  - Flynn PM
AD  - Translational Trials Unit, MS 600, St. Jude Children's Research Hospital, 262 
      Danny Thomas Place, Memphis, TN 38105, United States.
FAU - McCarthy, James S
AU  - McCarthy JS
AD  - Department of Clinical Tropical Medicine, QIMR Berghofer Medical Research 
      Institute, Herston, QLD, Australia.
FAU - Chalon, Stephan
AU  - Chalon S
AD  - Medicines for Malaria Venture, Geneva, Switzerland.
FAU - Guy, R Kiplin
AU  - Guy RK
AD  - University of Kentucky College of Pharmacy, Lexington, KY, United States.
LA  - eng
SI  - ClinicalTrials.gov/NCT02661373
GR  - P30 CA021765/CA/NCI NIH HHS/United States
PT  - Clinical Trial
PT  - Journal Article
DEP - 20220519
PL  - Netherlands
TA  - EBioMedicine
JT  - EBioMedicine
JID - 101647039
RN  - 0 (Antimalarials)
RN  - 0 (Folic Acid Antagonists)
RN  - 0 (Heterocyclic Compounds, 4 or More Rings)
RN  - 0 (Isoquinolines)
RN  - 0 (SJ733)
RN  - LW2E03M5PG (Cobicistat)
SB  - IM
MH  - *Antimalarials/adverse effects
MH  - Cobicistat/therapeutic use
MH  - *Folic Acid Antagonists
MH  - Heterocyclic Compounds, 4 or More Rings
MH  - Humans
MH  - Isoquinolines
MH  - *Malaria/drug therapy
MH  - *Malaria, Falciparum/drug therapy/parasitology
MH  - Plasmodium falciparum
PMC - PMC9127571
OTO - NOTNLM
OT  - Antimalarial
OT  - Pharmacoboost
OT  - Pharmacodynamics
OT  - Pharmacokinetics
OT  - SJ733
COIS- A.H.G. and BBF III received grant funding from the GHIT and MMV. J.C.P. received 
      grant funding from the GHIT and the NIH Cancer Center Support Grant P30 CA021765. 
      R.D., T.B.S., L.T., E.J., K.C.B., S.O., N.D.P., R.N.H., J.T.H., F.G., N.M., and 
      T.Y. received grant funding from the GHIT. P.M.F. is a member of the Merck Safety 
      Monitoring Committee. J.S.M. received funding from the Australian National Health 
      and Medical Research Council (NHMRC) Practitioner Fellowship (GNT1135955) and 
      NHMRC grant Programme (GNT1132975). R.K.G. receives grant funding from and is a 
      reviewer for the GHIT and MMV. He is also an inventor on a patent disclosing 
      SJ733, which may generate revenue if licensed. A.M.S., J.L.R, L.B., and S.C. have 
      no conflicts to declare.
EDAT- 2022/05/23 06:00
MHDA- 2022/06/15 06:00
PMCR- 2022/05/19
CRDT- 2022/05/22 18:13
PHST- 2022/01/13 00:00 [received]
PHST- 2022/04/07 00:00 [revised]
PHST- 2022/05/04 00:00 [accepted]
PHST- 2022/05/23 06:00 [pubmed]
PHST- 2022/06/15 06:00 [medline]
PHST- 2022/05/22 18:13 [entrez]
PHST- 2022/05/19 00:00 [pmc-release]
AID - S2352-3964(22)00246-8 [pii]
AID - 104065 [pii]
AID - 10.1016/j.ebiom.2022.104065 [doi]
PST - ppublish
SO  - EBioMedicine. 2022 Jun;80:104065. doi: 10.1016/j.ebiom.2022.104065. Epub 2022 May 
      19.