Sickle cell disease (SCD) is caused by an inherited structural abnormality of adult Hb causing polymerizationFetal Hb interferes with polymerization but is epigenetically silenced by DNA methyltransferase 1 (DNMT1) in adult erythropoiesis.Decitabine depletes DNMT1 and increases fetal and total Hb in SCD patients, but is rapidly catabolized by cytidine deaminase (CDA) in vivo.Tetrahydrouridine (THU) inhibits CDA, safeguarding decitabine.The pharmacokinetics and pharmacodynamics of three oral combination formulations of THU and decitabine, with different coatings producing different delays in decitabine release, were investigated in healthy participants.Tetrahydrouridine and decitabine were rapidly absorbed into the systemic circulation after a single combination oral dose, with relative bioavailability of decitabine ≥74% in fasted males compared with sep. oral administration of THU followed by decitabine 1 h later.THU and decitabine Cmax and area under the plasma concentration vs. time curve were higher in females vs. males, and fasted vs. fed states.Despite sex and food effect on pharmacokinetics, the pharmacodynamic effect of DNMT1 downregulation was comparable in males and females and fasted and fed states.Treatments were well tolerated.Combination oral formulations of THU with decitabine produced pharmacokinetics and pharmacodynamics suitable for oral DNMT1-targeted therapy.