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Article ; Online: Practical approaches to evaluating and optimizing brain exposure in early drug discovery.

Freeman, Burgess B / Yang, Lei / Rankovic, Zoran

2019 Volume 182, Page(s) 111643

Abstract: Developing drugs for CNS related diseases continues to be one of the most challenging endeavors in drug discovery. This is at least in part related to the existence of the Blood Brain Barrier (BBB), a complex multicellular organization that provides ... ...

Abstract	Developing drugs for CNS related diseases continues to be one of the most challenging endeavors in drug discovery. This is at least in part related to the existence of the Blood Brain Barrier (BBB), a complex multicellular organization that provides selective access to required nutrients and hormones, while removing waste and restricting exposure to potential harmful toxins, pathogens, and xenobiotics. Consequently, designing and selecting molecules that can overcame this protection system are unique and critical aspects of the CNS drug discovery. Here we review modern CNS pharmacokinetic concepts and methods suitable for early drug discovery, and medicinal chemistry strategies towards molecules with optimal CNS exposure.
MeSH term(s)	Animals ; Blood-Brain Barrier/drug effects ; Central Nervous System/drug effects ; Central Nervous System Agents/chemistry ; Central Nervous System Agents/pharmacology ; Drug Delivery Systems ; Drug Discovery ; Humans ; Molecular Structure ; Structure-Activity Relationship
Chemical Substances	Central Nervous System Agents
Language	English
Publishing date	2019-08-23
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	188597-2
ISSN	1768-3254 ; 0009-4374 ; 0223-5234
ISSN (online)	1768-3254
ISSN	0009-4374 ; 0223-5234
DOI	10.1016/j.ejmech.2019.111643
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Article ; Online: Differential Effects of JAK1 vs. JAK2 Inhibition in Mouse Models of Hemophagocytic Lymphohistiocytosis.

Keenan, Camille / Albeituni, Sabrin / Oak, Ninad / Stroh, Alexa N / Tillman, Heather / Wang, Yingzhe / Freeman, Burgess B / Alemán-Arteaga, Silvia / Meyer, Lauren K / Woods, Rolanda / Verbist, Katherine C / Zhou, Yinmei / Cheng, Cheng / Nichols, Kim E

Blood

2024

Abstract: Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in pre- ... ...

Abstract	Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in pre-clinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, the JAK2 inhibitor fedratinib and the JAK1/2 inhibitor ruxolitinib. All three drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFNg)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, where perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, while fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent pro-inflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology.
Language	English
Publishing date	2024-03-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023021046
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Article ; Online: Vitamin D levels do not cause vitamin-drug interactions with dexamethasone or dasatinib in mice.

Annu, Kavya / Yasuda, Kazuto / Caufield, William V / Freeman, Burgess B / Schuetz, Erin G

PloS one

2021 Volume 16, Issue 10, Page(s) e0258579

Abstract: Vitamin D3 (VD3) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD3 status on systemic ... ...

Abstract	Vitamin D3 (VD3) induces intestinal CYP3A that metabolizes orally administered anti-leukemic chemotherapeutic substrates dexamethasone (DEX) and dasatinib potentially causing a vitamin-drug interaction. To determine the impact of VD3 status on systemic exposure and efficacy of these chemotherapeutic agents, we used VD3 sufficient and deficient mice and performed pharmacokinetic and anti-leukemic efficacy studies. Female C57BL/6J and hCYP3A4 transgenic VD3 deficient mice had significantly lower duodenal (but not hepatic) mouse Cyp3a11 and hCYP3A4 expression compared to VD3 sufficient mice, while duodenal expression of Mdr1a, Bcrp and Mrp4 were significantly higher in deficient mice. When the effect of VD3 status on DEX systemic exposure was compared following a discontinuous oral DEX regimen, similar to that used to treat pediatric acute lymphoblastic leukemia patients, male VD3 deficient mice had significantly higher mean plasma DEX levels (31.7 nM) compared to sufficient mice (12.43 nM) at days 3.5 but not at any later timepoints. Following a single oral gavage of DEX, there was a statistically, but not practically, significant decrease in DEX systemic exposure in VD3 deficient vs. sufficient mice. While VD3 status had no effect on oral dasatinib's area under the plasma drug concentration-time curve, VD3 deficient male mice had significantly higher dasatinib plasma levels at t = 0.25 hr. Dexamethasone was unable to reverse the poorer survival of VD3 sufficient vs. deficient mice to BCR-ABL leukemia. In conclusion, although VD3 levels significantly altered intestinal mouse Cyp3a in female mice, DEX plasma exposure was only transiently different for orally administered DEX and dasatinib in male mice. Likewise, the small effect size of VD3 deficiency on single oral dose DEX clearance suggests that the clinical significance of VD3 levels on DEX systemic exposure are likely to be limited.
MeSH term(s)	Animals ; Dasatinib ; Female ; Male ; Mice ; Vitamin D
Chemical Substances	Vitamin D (1406-16-2) ; Dasatinib (RBZ1571X5H)
Language	English
Publishing date	2021-10-20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0258579
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Article ; Online: Baloxavir Treatment Delays Influenza B Virus Transmission in Ferrets and Results in Limited Generation of Drug-Resistant Variants.

Pascua, Philippe Noriel Q / Jones, Jeremy C / Marathe, Bindumadhav M / Seiler, Patrick / Caufield, William V / Freeman, Burgess B / Webby, Richard J / Govorkova, Elena A

Antimicrobial agents and chemotherapy

2021 Volume 65, Issue 11, Page(s) e0113721

Abstract: Clinical efficacy of the influenza antiviral baloxavir marboxil (baloxavir) is compromised by treatment-emergent variants harboring a polymerase acidic protein I38T (isoleucine-38-threonine) substitution. However, the fitness of I38T-containing influenza ...

Abstract	Clinical efficacy of the influenza antiviral baloxavir marboxil (baloxavir) is compromised by treatment-emergent variants harboring a polymerase acidic protein I38T (isoleucine-38-threonine) substitution. However, the fitness of I38T-containing influenza B viruses (IBVs) remains inadequately defined. After the pharmacokinetics of the compound were confirmed in ferrets, animals were injected subcutaneously with 8 mg/kg of baloxavir acid (BXA) at 24 h postinoculation with recombinant BXA-sensitive (BXA-
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; Antiviral Agents/therapeutic use ; Dibenzothiepins ; Drug Resistance, Viral/genetics ; Ferrets ; Humans ; Influenza B virus/genetics ; Influenza, Human/drug therapy ; Morpholines ; Pharmaceutical Preparations ; Pyridones/therapeutic use ; Time-to-Treatment ; Triazines/therapeutic use
Chemical Substances	Antiviral Agents ; Dibenzothiepins ; Morpholines ; Pharmaceutical Preparations ; Pyridones ; Triazines ; baloxavir (4G86Y4JT3F)
Language	English
Publishing date	2021-08-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/AAC.01137-21
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Einzelsignatur: Show issues

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Article ; Online: Author Correction: Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.

Nature medicine

2024 Volume 30, Issue 3, Page(s) 909–910

Language	English
Publishing date	2024-03-25
Publishing country	United States
Document type	Published Erratum
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/s41591-023-02778-7
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: RBM39 degrader invigorates natural killer cells to eradicate neuroblastoma despite cancer cell plasticity.

Singh, Shivendra / Fang, Jie / Jin, Hongjian / Van de Velde, Lee-Ann / Wu, Qiong / Cortes, Andrew / Morton, Christopher L / Woolard, Mary A / Quarni, Waise / Steele, Jacob A / Connelly, Jon P / He, Liusheng / Thorne, Rebecca / Turner, Gregory / Confer, Thomas / Johnson, Melissa / Caufield, William V / Freeman, Burgess B / Lockey, Timothy /

Pruett-Miller, Shondra M / Wang, Ruoning / Davidoff, Andrew M / Thomas, Paul G / Yang, Jun

bioRxiv : the preprint server for biology

2024

Abstract: The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains ...

Abstract	The cellular plasticity of neuroblastoma is defined by a mixture of two major cell states, adrenergic (ADRN) and mesenchymal (MES), which may contribute to therapy resistance. However, how neuroblastoma cells switch cellular states during therapy remains largely unknown and how to eradicate neuroblastoma regardless of their cell states is a clinical challenge. To better understand the lineage switch of neuroblastoma in chemoresistance, we comprehensively defined the transcriptomic and epigenetic map of ADRN and MES types of neuroblastomas using human and murine models treated with indisulam, a selective RBM39 degrader. We showed that cancer cells not only undergo a bidirectional switch between ADRN and MES states, but also acquire additional cellular states, reminiscent of the developmental pliancy of neural crest cells. The lineage alterations are coupled with epigenetic reprogramming and dependency switch of lineage-specific transcription factors, epigenetic modifiers and targetable kinases. Through targeting RNA splicing, indisulam induces an inflammatory tumor microenvironment and enhances anticancer activity of natural killer cells. The combination of indisulam with anti-GD2 immunotherapy results in a durable, complete response in high-risk transgenic neuroblastoma models, providing an innovative, rational therapeutic approach to eradicate tumor cells regardless of their potential to switch cell states.
Language	English
Publishing date	2024-03-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.03.21.586157
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Article ; Online: Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.

Nature communications

2024 Volume 15, Issue 1, Page(s) 3483

Abstract: Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing ... ...

Abstract	Chemical discovery efforts commonly target individual protein domains. Many proteins, including the EP300/CBP histone acetyltransferases (HATs), contain several targetable domains. EP300/CBP are critical gene-regulatory targets in cancer, with existing high potency inhibitors of either the catalytic HAT domain or protein-binding bromodomain (BRD). A domain-specific inhibitory approach to multidomain-containing proteins may identify exceptional-responding tumor types, thereby expanding a therapeutic index. Here, we discover that targeting EP300/CBP using the domain-specific inhibitors, A485 (HAT) or CCS1477 (BRD) have different effects in select tumor types. Group 3 medulloblastoma (G3MB) cells are especially sensitive to BRD, compared with HAT inhibition. Structurally, these effects are mediated by the difluorophenyl group in the catalytic core of CCS1477. Mechanistically, bromodomain inhibition causes rapid disruption of genetic dependency networks that are required for G3MB growth. These studies provide a domain-specific structural foundation for drug discovery efforts targeting EP300/CBP and identify a selective role for the EP300/CBP bromodomain in maintaining genetic dependency networks in G3MB.
MeSH term(s)	Humans ; Medulloblastoma/genetics ; Medulloblastoma/drug therapy ; Medulloblastoma/metabolism ; Medulloblastoma/pathology ; E1A-Associated p300 Protein/metabolism ; E1A-Associated p300 Protein/genetics ; E1A-Associated p300 Protein/antagonists & inhibitors ; Cell Line, Tumor ; Gene Regulatory Networks/drug effects ; Animals ; Protein Domains ; Gene Expression Regulation, Neoplastic/drug effects ; Mice ; Cerebellar Neoplasms/genetics ; Cerebellar Neoplasms/drug therapy ; Cerebellar Neoplasms/metabolism ; Cerebellar Neoplasms/pathology ; Antineoplastic Agents/pharmacology
Chemical Substances	E1A-Associated p300 Protein (EC 2.3.1.48) ; EP300 protein, human (EC 2.3.1.48) ; Antineoplastic Agents
Language	English
Publishing date	2024-04-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-47102-0
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Article ; Online: Combination of Ribociclib with BET-Bromodomain and PI3K/mTOR Inhibitors for Medulloblastoma Treatment In Vitro and In Vivo.

Jonchere, Barbara / Williams, Justin / Zindy, Frederique / Liu, Jingjing / Robinson, Sarah / Farmer, Dana M / Min, Jaeki / Yang, Lei / Stripay, Jennifer L / Wang, Yingzhe / Freeman, Burgess B / Yu, Jiyang / Shelat, Anang A / Rankovic, Zoran / Roussel, Martine F

Molecular cancer therapeutics

2022 Volume 22, Issue 1, Page(s) 37–51

Abstract: Despite improvement in the treatment of medulloblastoma over the last years, numerous patients with MYC- and MYCN-driven tumors still fail current therapies. Medulloblastomas have an intact retinoblastoma protein RB, suggesting that CDK4/6 inhibition ... ...

Abstract	Despite improvement in the treatment of medulloblastoma over the last years, numerous patients with MYC- and MYCN-driven tumors still fail current therapies. Medulloblastomas have an intact retinoblastoma protein RB, suggesting that CDK4/6 inhibition might represent a therapeutic strategy for which drug combination remains understudied. We conducted high-throughput drug combination screens in a Group3 (G3) medulloblastoma line using the CDK4/6 inhibitor (CDK4/6i) ribociclib at IC20, referred to as an anchor, and 87 oncology drugs approved by FDA or in clinical trials. Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclib inhibition of proliferation in an established cell line and freshly dissociated tumor cells from intracranial xenografts of G3 and Sonic hedgehog (SHH) medulloblastomas in vitro. A reverse combination screen using the BET inhibitor JQ1 as anchor, revealed CDK4/6i as the most potentiating drugs. In vivo, ribociclib showed single-agent activity in medulloblastoma models whereas JQ1 failed to show efficacy due to high clearance and insufficient free brain concentration. Despite in vitro synergy, combination of ribociclib with the PI3K/mTOR inhibitor paxalisib did not significantly improve the survival of G3 and SHH medulloblastoma-bearing mice compared with ribociclib alone. Molecular analysis of ribociclib and paxalisib-treated tumors revealed that E2F targets and PI3K/AKT/MTORC1 signaling genes were depleted, as expected. Importantly, in one untreated G3MB model HD-MB03, the PI3K/AKT/MTORC1 gene set was enriched in vitro compared with in vivo suggesting that the pathway displayed increased activity in vitro. Our data illustrate the difficulty in translating in vitro findings in vivo. See related article in Mol Cancer Ther (2022) 21(8):1306-1317.
MeSH term(s)	Animals ; Humans ; Mice ; Cerebellar Neoplasms/drug therapy ; Gemcitabine ; Hedgehog Proteins ; Mechanistic Target of Rapamycin Complex 1 ; Medulloblastoma/genetics ; MTOR Inhibitors ; Phosphatidylinositol 3-Kinases/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Proto-Oncogene Proteins c-akt ; TOR Serine-Threonine Kinases/therapeutic use
Chemical Substances	Gemcitabine ; Hedgehog Proteins ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1) ; MTOR Inhibitors ; MTOR protein, human (EC 2.7.1.1) ; Phosphatidylinositol 3-Kinases (EC 2.7.1.-) ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; ribociclib (TK8ERE8P56) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-10-31
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-21-0896
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Article ; Online: ATM inhibition enhances the efficacy of radiation across distinct molecular subgroups of pediatric high-grade glioma.

Neuro-oncology

2023 Volume 25, Issue 10, Page(s) 1828–1841

Abstract: Background: Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to ... ...

Abstract	Background: Pediatric high-grade glioma (pHGG) is largely incurable and accounts for most brain tumor-related deaths in children. Radiation is a standard therapy, yet the benefit from this treatment modality is transient, and most children succumb to disease within 2 years. Recent large-scale genomic studies suggest that pHGG has alterations in DNA damage response (DDR) pathways that induce resistance to DNA damaging agents. The aim of this study was to evaluate the therapeutic potential and molecular consequences of combining radiation with selective DDR inhibition in pHGG. Methods: We conducted an unbiased screen in pHGG cells that combined radiation with clinical candidates targeting the DDR and identified the ATM inhibitor AZD1390. Subsequently, we profiled AZD1390 + radiation in an extensive panel of early passage pHGG cell lines, mechanistically characterized response to the combination in vitro in sensitive and resistant cells and evaluated the combination in vivo using TP53 wild-type and TP53 mutant orthotopic xenografts. Results: AZD1390 significantly potentiated radiation across molecular subgroups of pHGG by increasing mutagenic nonhomologous end joining and augmenting genomic instability. In contrast to previous reports, ATM inhibition significantly improved the efficacy of radiation in both TP53 wild-type and TP53 mutant isogenic cell lines and distinct orthotopic xenograft models. Furthermore, we identified a novel mechanism of resistance to AZD1390 + radiation that was marked by an attenuated ATM pathway response which dampened sensitivity to ATM inhibition and induced synthetic lethality with ATR inhibition. Conclusions: Our study supports the clinical evaluation of AZD1390 in combination with radiation in pediatric patients with HGG.
MeSH term(s)	Humans ; Child ; Glioma/drug therapy ; Glioma/genetics ; Glioma/radiotherapy ; Brain Neoplasms/drug therapy ; Brain Neoplasms/genetics ; Brain Neoplasms/radiotherapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; DNA Damage ; Ataxia Telangiectasia Mutated Proteins/genetics ; Ataxia Telangiectasia Mutated Proteins/metabolism
Chemical Substances	Protein Kinase Inhibitors ; ATM protein, human (EC 2.7.11.1) ; Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
Language	English
Publishing date	2023-03-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/noad064
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Article ; Online: Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with the pharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drug development.

EBioMedicine

2022 Volume 80, Page(s) 104065

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 ... ...

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 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.
MeSH term(s)	Antimalarials/adverse effects ; Cobicistat/therapeutic use ; Folic Acid Antagonists ; Heterocyclic Compounds, 4 or More Rings ; Humans ; Isoquinolines ; Malaria/drug therapy ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/parasitology ; Plasmodium falciparum
Chemical Substances	Antimalarials ; Folic Acid Antagonists ; Heterocyclic Compounds, 4 or More Rings ; Isoquinolines ; SJ733 ; Cobicistat (LW2E03M5PG)
Language	English
Publishing date	2022-05-19
Publishing country	Netherlands
Document type	Clinical Trial ; Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2022.104065
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