UGT1A1 genotype-dependent dose adjustment of belinostat in patients with advanced cancers using population pharmacokinetic modeling and simulation. | LitMetric
Belinostat is a second-generation zinc-binding histone deacetylase inhibitor that is approved for peripheral T-cell lymphoma and is currently being studied in small cell lung cancer and other advanced carcinomas as a 48-hour continuous intravenous infusion. Belinostat is predominantly metabolized by UGT1A1, which is polymorphic. Preliminary analyses revealed a difference in belinostat clearance based on UGT1A1 genotype. A 2-compartment population pharmacokinetic (PK) model was developed and validated that incorporated the UGT1A1 genotype, albumin, and creatinine clearance on the clearance parameter; body weight was a significant covariate on volume. Simulated doses of 600 and 400 mg/m(2) /24 h given to patients considered extensive or impaired metabolizers, respectively, provided equivalent AUCs. This model and subsequent simulations supported additional PK/toxicity and pharmacogenomics/toxicity analyses to suggest a UGT1A1 genotype-based dose adjustment to normalize belinostat exposure and allow for more tolerable therapy. In addition, global protein lysine acetylation was modeled with PK and demonstrated a reversible belinostat exposure/response relationship, consistent with previous reports.
Background: The 15° left tilt position during caesarean delivery has been recommended by guidelines for many years, but recent studies have questioned the clinical benefit of left tilt position. We hypothesize that using a higher starting dose of metaraminol in the supine position will result in a non-inferior umbilical arterial pH, compared to the 15° left tilt position.
Methods: Healthy women undergoing elective caesarean delivery were randomized to the supine position (n = 62) or 15° left tilt position (n = 62) after spinal anaesthesia (0.
Background: The association between the triglyceride-glucose (TyG) index and mortality in the general population remains controversial, with inconsistent findings across studies.
Objective: This study aims to investigate the relationship between the TyG index and mortality in the U.S.
Instituto de Investigación Sanitaria de Canarias, Carretera Gral. La Cuesta-Taco, n.s/n Pabellón de Gobierno del HUC Planta -1ª, 38320, San Cristobal de La Laguna, Santa Cruz de, Tenerife, Spain.
Objectives: To evaluate the rationality of the clinical use of ceftazidime-avibactam (CAZ-AVI) for carbapenem-resistant Klebsiella pneumoniae (CRKP) infections in a real-world setting.
Methods: We established the rational evaluation criteria based on drug instructions and relevant guidelines to retrospectively evaluate the use of CAZ-AVI to treat CRKP infections from June 2020 to June 2023 in a tertiary hospital in China. Patients were divided into the rational use group and irrational use group.
Background: The simultaneous differentiation of human pluripotent stem cells (hPSCs) into both endodermal and mesodermal lineages is crucial for developing complex, vascularized tissues, yet poses significant challenges. This study explores a method for co-differentiation of mesoderm and endoderm, and their subsequent differentiation into pancreatic progenitors (PP) with endothelial cells (EC).
