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

Abstract

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.3–5 Aims: Building on previous work examining oral administration of THU and decitabine separated by 1 hour,3 this study evaluated the pharmacokinetics, pharmacodynamics, and safety of three test formulations of a combination capsule with delayed-release decitabine and THU. This will inform development of an optimum oral combination formulation that is more practical for evaluation, adherence, and clinical use. Methods: The pharmacokinetics and pharmacodynamics of three test formulations of a combination capsule with delayed-release decitabine and THU were investigated in two phase 1 studies: one in healthy adult males (n=16) under fasting conditions (NCT03828084) vs a reference treatment of THU followed 1 hour (±5 min) later by decitabine; and one in healthy adult males and females (n=48) under fed and fasting conditions (NCT04086238). The three combined formulations (designated A, B, C) differed by composition of the coating, producing different delays in decitabine release: treatment A provided the least delay in decitabine release and treatment C the greatest. The reference treatment was designated D. Results: A single, combined oral dose led to rapid absorption of THU and decitabine into systemic circulation (Figure). The relative bioavailability of decitabine in plasma was ≥74% in fasted males, compared with separate oral administration of THU followed by decitabine 1 hour later. Higher THU and decitabine maximum concentration (Cmax) and area under the plasma concentration–time curve (AUC) were observed in females vs males, and fasted vs fed states. In the fed state, decitabine Cmax and AUC were comparable between males and females for formulations A and B. Despite a food effect on pharmacokinetics, the pharmacodynamic effect of DNMT1 downregulation post-dose was comparable in both fasted and fed states. The combination formulations and the reference treatment were well tolerated. Treatment-emergent adverse events were mild or moderate with no serious adverse events. Platelet and neutrophil counts did not change significantly. Conclusion: The combination formulation of THU with decitabine produced pharmacokinetics and pharmacodynamics suitable for oral DNMT1-targeted therapy, the goal of which is to increase fetal hemoglobin in people with SCD. The safety and efficacy of a combination formulation developed based on these results is being evaluated in the phase 2 trial ASCENT1 (NCT05405114).