A5065194510- DNA Repair Mechanisms
- Cancer, Hypoxia, and Metabolism
- Mitochondrial Function and Pathology
- Protein Interaction Studies and Fluorescence Analysis
- Antibiotics Pharmacokinetics and Efficacy
- PARP inhibition in cancer therapy
- Inhalation and Respiratory Drug Delivery
- Phytoestrogen effects and research
- Drug Solubulity and Delivery Systems
- Phagocytosis and Immune Regulation
- Drug Transport and Resistance Mechanisms
- Chronic Lymphocytic Leukemia Research
- Nanoparticle-Based Drug Delivery
- Pharmaceutical studies and practices
- Cancer-related Molecular Pathways
- Advanced Drug Delivery Systems
- Antibiotic Resistance in Bacteria
- Pharmacogenetics and Drug Metabolism
- Glutathione Transferases and Polymorphisms
- Nuclear Receptors and Signaling
- Ion Transport and Channel Regulation
- Cancer Genomics and Diagnostics
- Biosimilars and Bioanalytical Methods
- Cytokine Signaling Pathways and Interactions
- Glioma Diagnosis and Treatment
Ono Pharmaceutical (United States)
2022-2024
Research & Development Institute
2022-2024
Merck (Germany)
2024
Takeda (United States)
2022
Central Drug Research Institute
2021
Boehringer Ingelheim (United States)
2019
University of Florida
2014-2017
University of Saskatchewan
2010-2015
Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy of tuvusertib monotherapy.
Background: The modeling of drug effects on myelopoiesis is widely used to inform dose and schedule optimization in development. While many examples exist for neutropenia, applications describing anemia are fewer, with delayed attainment peak effect hemoglobin (HGB) introducing additional complexity when analyzing short-term data early clinical Tuvusertib a potent, selective, orally administered ATR inhibitor currently phase1/2 Anemia has been reported as limiting toxicity during the...
Dry powder inhalations (DPI) of microparticles containing isoniazid (INH) and rifabutin (RFB) are under preclinical development for use in pulmonary tuberculosis. Microparticles 0.25, 2.5, or 25 mg each drug were administered daily 90 days to rhesus macaques (n = 4/group). Single intravenous (i.v.) doses separate groups. Drugs serum, alveolar macrophages, organ homogenates assayed by high-performance liquid chromatography (HPLC). The RFB/INH the lungs (101.10 ± 12.90/101.07 8.09 μg/g tissue)...
Reports in the literature associate dietary intake of flaxseed lignans with a number health benefits. The major lignan found flaxseed, secoisolariciresinol diglucoside (1), undergoes metabolism principally to (2), enterodiol (3), and enterolactone (4) human gastrointestinal tract. Systemically, are present largely as phase II enzyme conjugates. To improve understanding oral absorption characteristics, systematic evaluation intestinal permeation was conducted conjugative potential these using...
Consumption of flaxseed lignans is associated with various health benefits; however, little known about the bioavailability purified in flaxseed. Data on their and hence pharmacokinetics (PK) are necessary to better understand role putative benefits. In present study, we conducted a comparative PK analysis principal lignan flaxseed, secoisolariciresinol diglucoside (SDG), its primary metabolites, (SECO), enterodiol (ED) enterolactone (EL) rats. Purified were intravenously or orally...
Abstract Ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) protein kinases are critical in the DNA damage response. ATR ATM genes have a synthetic lethal relationship cancer ATMi synergistically potentiates efficacy of ATRi vitro vivo. Here, we studied combination potential highly potent, oral agents tuvusertib lartesertib. The open-label, multicenter study DDRiver Solid Tumors 320 (NCT05396833) investigated safety, tolerability, PK PD + lartesertib pts with advanced solid tumors...
3018 Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase poly-ADP ribose polymerases (PARPs) are crucial components in the DNA damage response (DDR). Combining tuvusertib niraparib may synergistically enhance synthetic lethality increase apoptosis. Part B1 of DDRiver Solid Tumors 301 study (NCT04170153) assessed this combination. Methods: open-label multicenter dose-escalation phase Ib trial enrolled unselected patients with metastatic or locally advanced unresectable...
Abstract M4076 is a potent and selective oral inhibitor of ataxia-telangiectasia mutated (ATM), key kinase the DNA damage response (DDR) involved in double-strand break repair. Preclinically, when combined with damage-inducing therapy or other DDR inhibitors caused unrestricted cell cycle progression accumulation, resulting tumor death. Part 1A this ongoing open-label study (NCT04882917) evaluated safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), maximum tolerated dose...
Trazpiroben is a dopamine D2 /D3 receptor antagonist under development for the treatment of gastroparesis. This phase I, open-label, randomized, two-way crossover study (NCT04121078) evaluated effect single-dose intravenous rifampin, potent inhibitor organic anion transporting polypeptides (OATPs) 1B1 and 1B3, on pharmacokinetics safety trazpiroben in healthy adults. The utility coproporphyrin (CP) I CPIII as biomarkers OATP inhibition was also assessed. Overall, 12 participants were...
Abstract Background: Ataxia telangiectasia and Rad3-related (ATR) protein kinase plays a critical role in the DNA damage response. M1774, potent, selective, orally administered ATR inhibitor with antitumor activity preclinical models, was evaluated Part A1 of an open-label, single-arm study (NCT04170153) for safety, tolerability, maximum tolerated dose, pharmacokinetics (PK) pharmacodynamics (PD). M1774 monotherapy patients advanced solid tumors well-tolerated totality evidence, including...
Abstract Introduction: In cancer therapy, combinations of drugs interfering with different molecular pathways enhance efficacy and reduce resistance development, but may also increase the risk toxicity. DNA damage repair inhibitors (DDRi) induce on- off-target adverse events including hematological gastro-intestinal toxicities1, which impact therapeutic window. We evaluated hematopoietic effect ATRi tuvusertib ATMi lartesertib, alone in combination, on erythroid, megakaryocytic myeloid bone...
<div>AbstractPurpose:<p>Tuvusertib (M1774) is a potent, selective, orally administered ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. This first-in-human study (NCT04170153) evaluated safety, tolerability, maximum tolerated dose (MTD), recommended for expansion (RDE), pharmacokinetics (PK), pharmacodynamics (PD), preliminary efficacy of tuvusertib monotherapy.</p>Patients Methods:<p>Ascending doses were in 55 patients with metastatic or locally...