Clinical activity, pharmacokinetics, and pharmacodynamics of oral hypomethylating agents for myelodysplastic syndromes/neoplasms and acute myeloid leukemia: A multidisciplinary review.

Objective: To review the pharmacokinetic (PK)-pharmacodynamic (PD) profiles, disease setting, dosing, and safety of oral and parenteral hypomethylating agents (HMAs) for the treatment of myelodysplastic syndromes/neoplasms (MDS) and acute myeloid leukemia (AML), and to provide a multidisciplinary perspective on treatment selection and educational needs relating to HMA use.
Data Sources: Clinical and real-world data for parenteral decitabine and azacitidine and two oral HMAs: decitabine-cedazuridine (DEC-C) for MDS and azacitidine (CC-486) for AML maintenance therapy.
Data Summary: Differences in the PK-PD profiles of oral and parenteral HMA formulations have implications for their potential toxicities and planned use. Oral DEC-C (decitabine 35 mg and cedazuridine 100 mg) has demonstrated equivalent systemic area under the concentration-time curve (AUC) exposure to a 5-day regimen of intravenous (IV) decitabine 20 mg/m ² and showed no significant difference in PD. The AUC equivalence of oral DEC-C and IV decitabine means that these regimens can be treated interchangeably (but must not be substituted within a cycle). Oral azacitidine has a distinct PK-PD profile versus IV or subcutaneous azacitidine, and the formulations are not bioequivalent or interchangeable owing to differences in plasma time-course kinetics and exposures. Clinical trials are ongoing to evaluate oral HMA combinations and novel oral HMAs, such as NTX-301 and ASTX030.
Conclusions: Treatment with oral HMAs has the potential to improve quality of life, treatment adherence, and disease outcomes versus parenteral HMAs. Better education of multidisciplinary teams on the factors affecting HMA treatment selection may help to improve treatment outcomes in patients with MDS or AML.
Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JK-S is Chair of the Summit & Julie Shah Foundation; is a member of Clinica Latina Board and Columbus Free Clinic Board; and has received honoraria or support for attending meetings from Hematology/Oncology Pharmacy Association and Vizient. AMZ is a Leukemia and Lymphoma Society Scholar in Clinical Research; has received research funding (institutional) from Abbvie, Aprea, Astex, BeyondSpring, Boehringer-Ingelheim, Celgene/BMS, Foran, Geron, Incyte, Kura, Medimmune/AstraZeneca, Novartis, Pfizer, Shattuck Labs, and Takeda; has received honoraria from AbbVie, Agios, ALX Oncology, Amgen, Astellas, BioCryst, Boehringer-Ingelheim, Celgene/BMS, Chiesi, Daiichi Sankyo, Epizyme, Genentech, Geron, Gilead, Incyte, Ionis, Janssen, Jazz, Kura, Mendus, Notable, Novartis, Orum, Otsuka, Pfizer, Regeneron, Schrodinger, Seattle Genetics, Servier, Syndax, Syros, Taiho Oncology, Takeda, Tyme, and Zentalis; and has served on clinical trial committees for Abbvie, ALX Oncology, BioCryst, Celgene/BMS, Geron, Gilead, Kura, Novartis, and Syros. RH and LB have no relevant conflicts of interest.