5613127 PHARMACOKINETICS AND PHARMACODYNAMICS OF AN INNOVATIVE ORAL FORMULATION OF DECITABINE AND TETRAHYDROURIDINE IN HEALTHY PEOPLE

摘要: Background: Sickle cell disease (SCD) pathophysiology emerges from an inherited structural abnormality of adult hemoglobin that causes it to polymerize when deoxygenated, forcing red blood cells (RBCs) into a sickled conformation. 1 Sickled RBCs are rigid, damage vessel endothelium, are less able to flow, and are more likely to hemolyze than healthy RBCs. 1 Fetal hemoglobin interferes with polymerization but is epigenetically silenced by DNA methyltransferase 1 (DNMT1) in adult (post-fetal) erythropoiesis. 2 Decitabine, a DNMT1 inhibitor, can increase fetal and total hemoglobin in people with SCD; however in vivo it is rapidly catabolized by cytidine deaminase (CDA). 3 Tetrahydrouridine (THU) inhibits CDA thus safeguarding and thereby increasing the bioavailability of decitabine. 3–5Aims: Building on previous work examining oral administration of THU and decitabine separated by 1 hour, 3 this study …