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 McCarthy; Stephan Chalon; R Kiplin Guy

doi:10.1016/j.ebiom.2022.104065

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 McCarthy

Stephan Chalon, R Kiplin Guy

Producción científica: Article › revisión exhaustiva

16 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	104065
Publicación	EBioMedicine
Volumen	80
DOI	https://doi.org/10.1016/j.ebiom.2022.104065
Estado	Published - jun 2022

Nota bibliográfica

Financiación

This study was supported by funds from the GHIT (Grant G2016-226), MMV (Grant 181571010), NIH Cancer Center Support Grant P30 CA021765, and ALSAC. The authors thank Tim Folse, MD, for assistance with participant screening; Robbin Christensen, BSPharm, for investigational drug pharmacy support, Angela J. McArthur, PhD, ELS, for Scientific Editing support; and all staff from the Office of Clinical Research, University of Tennessee Health Science Center who helped with the conduct of study activities. The authors also thank the participants who volunteered for this study. 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. This study was supported by funds from the GHIT (Grant G2016-226 ), MMV ( Grant 181571010 ), NIH Cancer Center Support Grant P30 CA021765 , and ALSAC. The authors thank Tim Folse, MD, for assistance with participant screening; Robbin Christensen, BSPharm, for investigational drug pharmacy support, Angela J. McArthur, PhD, ELS, for Scientific Editing support; and all staff from the Office of Clinical Research, University of Tennessee Health Science Center who helped with the conduct of study activities. The authors also thank the participants who volunteered for this study.

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Gaur, A. H., Panetta, J. C., Smith, A. M., Dallas, R. H., Freeman, B. B., Stewart, T. B., Tang, L., John, E., Branum, K. C., Patel, N. D., Ost, S., Heine, R. N., Richardson, J. L., Hammill, J. T., Bebrevska, L., Gusovsky, F., Maki, N., Yanagi, T., Flynn, P. M., ... Guy, R. K. (2022). Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development. EBioMedicine, 80, 104065. https://doi.org/10.1016/j.ebiom.2022.104065

@article{514ab79f375d4bf2a963f96aa093685e,

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

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.",

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",

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

year = "2022",

month = jun,

doi = "10.1016/j.ebiom.2022.104065",

language = "English",

volume = "80",

pages = "104065",

}

Gaur, AH, Panetta, JC, Smith, AM, Dallas, RH, Freeman, BB, Stewart, TB, Tang, L, John, E, Branum, KC, Patel, ND, Ost, S, Heine, RN, Richardson, JL, Hammill, JT, Bebrevska, L, Gusovsky, F, Maki, N, Yanagi, T, Flynn, PM, McCarthy, JS, Chalon, S & Guy, RK 2022, 'Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development', EBioMedicine, vol. 80, pp. 104065. https://doi.org/10.1016/j.ebiom.2022.104065

TY - JOUR

T1 - Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat

T2 - An innovative approach in antimalarial drug development

AU - Gaur, Aditya H

AU - Panetta, John C

AU - Smith, Amber M

AU - Dallas, Ronald H

AU - Freeman, Burgess B

AU - Stewart, Tracy B

AU - Tang, Li

AU - John, Elizabeth

AU - Branum, Kristen C

AU - Patel, Nehali D

AU - Ost, Shelley

AU - Heine, Ryan N

AU - Richardson, Julie L

AU - Hammill, Jared T

AU - Bebrevska, Lidiya

AU - Gusovsky, Fabian

AU - Maki, Noritsugu

AU - Yanagi, Toshiharu

AU - Flynn, Patricia M

AU - McCarthy, James S

AU - Chalon, Stephan

AU - Guy, R Kiplin

PY - 2022/6

Y1 - 2022/6

N2 - 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.

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 × 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.

KW - Antimalarials/adverse effects

KW - Cobicistat/therapeutic use

KW - Folic Acid Antagonists

KW - Heterocyclic Compounds, 4 or More Rings

KW - Humans

KW - Isoquinolines

KW - Malaria/drug therapy

KW - Malaria, Falciparum/drug therapy

KW - Plasmodium falciparum

U2 - 10.1016/j.ebiom.2022.104065

DO - 10.1016/j.ebiom.2022.104065

M3 - Article

C2 - 35598441

VL - 80

SP - 104065

JO - EBioMedicine

JF - EBioMedicine

ER -

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

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