A5052027970- PARP inhibition in cancer therapy
- PI3K/AKT/mTOR signaling in cancer
- Melanoma and MAPK Pathways
- Antibiotics Pharmacokinetics and Efficacy
- Pneumonia and Respiratory Infections
- Colorectal Cancer Treatments and Studies
- HER2/EGFR in Cancer Research
- Antibiotic Resistance in Bacteria
- Toxin Mechanisms and Immunotoxins
- Ovarian cancer diagnosis and treatment
- Cancer Mechanisms and Therapy
- Protein Degradation and Inhibitors
- Neuroblastoma Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer Treatment and Pharmacology
- DNA Repair Mechanisms
- Hepatocellular Carcinoma Treatment and Prognosis
- Neurofibromatosis and Schwannoma Cases
- Ion channel regulation and function
- Prostate Cancer Treatment and Research
- Prostate Cancer Diagnosis and Treatment
- Quinazolinone synthesis and applications
- BRCA gene mutations in cancer
- Cell death mechanisms and regulation
- Cardiac electrophysiology and arrhythmias
AstraZeneca (United Kingdom)
2013-2024
Institut Bergonié
2018
Samsung Medical Center
2018
Institut Claudius Regaud
2018
Institut Gustave Roussy
2018
The Christie NHS Foundation Trust
2018
Hôpital Cochin
2018
Seoul National University Hospital
2018
Virginia Commonwealth University
2011
University of North Carolina at Chapel Hill
2011
PURPOSE Hepatocellular carcinoma (HCC) is a common and deadly malignancy with few systemic therapy options. The RAF/mitogen-activated protein kinase (MEK)/extracellular signal-related (ERK) pathway activated in approximately 50% to 60% of HCCs represents potential target for therapy. Selumetinib an orally available inhibitor MEK tyrosine activity. PATIENTS AND METHODS Patients locally advanced or metastatic HCC who had not been treated prior were enrolled on the study. selumetinib at its...
KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and AKT inhibitors (such as MK-2206), combination of which overcome both monotherapies.
The aim of this Phase 1, open-label study (NCT01395420) was to measure and compare concentrations ceftazidime avibactam in bronchial epithelial lining fluid (ELF) plasma, following administration two different dosing regimens healthy subjects. Healthy volunteers received 2000 mg + 500 (n = 22) or 3000 1000 21), administered intravenously every 8 h for 3 days (total nine doses). Bronchoscopy with bronchoalveolar lavage performed once per subject, 2, 4, 6 after the last infusion....
We report physiologically based pharmacokinetic‐modeling analyses to determine olaparib (tablet or capsule) drug–drug interactions (DDIs). Verified DDI simulations provided dose recommendations for coadministration with clinically relevant CYP3A4 modulators eliminate potential risk patient safety efficacy. When is given strong/moderate CYP3A inhibitors, the should be reduced 100/150 mg b.i.d. (tablet), and 150/200 (capsule). Olaparib administration not recommended inducers. No reductions are...
Abstract Background Olaparib is a potent poly(ADP-ribose) polymerase (PARP) inhibitor, with first-in-class approval (400 mg capsules BID) for BRCA-mutated advanced ovarian cancer. was recently found to be superior compared chemotherapy in HER2-negative gBRCAm MBC the Phase III OlympiAD trial. induces DNA damage and genomic instability tumors, which hypothesized result enhanced immunogenicity. Here, we assess if combination of olaparib an anti-programmed cell death ligand-1 (PD-L1) agent,...
Abstract We assessed pharmacokinetic and safety profiles of ceftazidime–avibactam administered ± metronidazole, whether drug–drug interactions exist between ceftazidime avibactam, or ceftazidime‐avibactam metronidazole. The first study (NCT01430910) involved two cohorts healthy subjects. Cohort 1 received (2000–500 mg) as a single infusion multiple intravenous infusions over 11 days to evaluate pharmacokinetics. 2 ceftazidime, 4 assess interaction avibactam. second ( NCT 01534247)...
This Phase I study assessed whether food influences the rate and extent of selumetinib absorption in patients with advanced solid malignancies determined safety, tolerability, pharmacokinetic (PK) profile its active metabolite N-desmethyl-selumetinib fed fasted states.A single dose 75 mg was to be taken on Day 1 followed by a after fasting for at least 10 h 8, or vice versa, twice daily dosing from 10. Plasma concentrations PK parameters were Days 8. Patients could continue receive as long...
1. In vitro studies were conducted to evaluate potential inhibitory and inductive effects of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib, on cytochrome P450 (CYP) enzymes. Inhibitory determined in human liver microsomes (HLM); evaluated cultured hepatocytes. 2. Olaparib did not inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2D6 or CYP2E1 caused slight inhibition CYP2C9, CYP2C19 CYP3A4/5 HLM up a concentration 100 μM. However, olaparib (17-500 μM) inhibited with an IC50 119...
Olaparib, a potent oral poly(ADP-ribose) polymerase inhibitor, is partially hepatically cleared. We investigated the pharmacokinetics (PK) and safety of olaparib in patients with mild or moderate hepatic impairment to provide dosing recommendations.This Phase I open-label study assessed PK, tolerability single doses 300-mg tablets advanced solid tumours. Patients had normal function (NHF), (MiHI; Child-Pugh class A) (MoHI; B) impairment. Blood was collected for PK assessments 96 hours. could...
Abstract Background Selumetinib is approved for the treatment of pediatric patients with neurofibromatosis type 1 (NF1) who have symptomatic, inoperable plexiform neurofibromas (PN) in multiple countries, including USA (≥ 2 years). Until recently, individuals had to take selumetinib twice daily (BID) a fasted state. This study evaluated effect low-fat meal on PK parameters and gastrointestinal (GI) tolerability adolescent participants NF1-PN. Methods Eligible aged ≥ 12 < 18 years took...
3105 Background: AZD8931 is an oral, equipotent inhibitor of ErbB1, ErbB2 and ErbB3 receptor signaling. Methods: This open-label (3+3 design) study (NCT00900627) evaluated the MTD, safety, tolerability PK (40–160 mg bid) combined with P (90 mg/m2 on days 1, 8 15 a 28-day cycle). DLTs were during Cycle 1. dosing started at 160 bid (based monotherapy results; NCT00637039). Results: 20 pts advanced refractory tumors (16 breast) received AZD8931. Median exposure to was 52 3 cycles. In cohort,...
Background. Selumetinib, a mitogen-activated protein kinase 1/2 inhibitor, has been approved in several countries and regions, including Japan, for the treatment of pediatric patients with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas at body surface area (BSA)-based dose 25 mg/m2 twice daily. The objective this population pharmacokinetic analysis was to evaluate ethnic sensitivity pharmacokinetics selumetinib N-desmethyl between Japanese non-Japanese...
2562 Background: The PARP inhibitorolaparib (Lynparza) is being evaluated in combination with other anticancer agents. We investigated the steady-state (ss) PK effects and safety of olaparib (tablet) co-administered anti-hormonal agents tamoxifen, anastrozole, or letrozole. Methods: An open-label, nonrandomized study was conducted 79 eligible patients advanced solid tumors. During three consecutive treatment periods, received: (1) 300 mg twice daily (bd) for 5 days, followed by a 4-day...