A Comparative Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of Azacitidine Following Subcutaneous (SC) and Oral Administration in Subjects with Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML), Results From a Phase 1 Study

• Published in: Blood 2009-11, Vol.114 (22), p.1772-1772
• Main Authors: MacBeth, Kyle J, Laille, Eric, Ning, Yuhong, Cogle, Christopher R., Skikne, Barry, Gore, Steven D., Garcia-Manero, Guillermo, Ward, M. Renee
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V114.22.1772.1772

Abstract 1772 Poster Board I-798 Parenteral azacitidine significantly improves overall survival in patients with higher-risk MDS and WHO AML (20-30% blasts) compared to conventional care (Fenaux, Lancet Oncol 2009;10:223). An oral azacitidine formulation is in development. A Phase 1, “3+3”, dose-escalation study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), safety, PK and PD profiles of SC and increasing doses of orally-administered azacitidine in subjects with MDS or AML (not candidates for other therapies) by WHO criteria. In this study, each subject served as their own control and received SC azacitidine in Cycle 1 followed by oral azacitidine in subsequent cycles (Cycle 2+). PK and PD were evaluated in blood, following SC and oral administration. DNA methylation patterns in blood pre- and post-treatment (SC and oral) were explored to build an understanding of how DNA methylation may relate to azacitidine PK parameters. Azacitidine was administered SC (75 mg/m2/day x 7 days) in Cycle 1, then orally in Cycle 2 starting at a dose of 120 mg/day x 7 days of every 28-day cycle. PK parameters were derived from azacitidine concentrations in plasma and urine collected after the first and last dose. Samples collected in Cycles 1 and 2 were assayed for DNA methylation using Illumina's Infinium Human Methylation27 BeadArrays, which provide methylation levels for >27,000 CpG loci. A linear models for microarray analysis (LIMMA) was performed to identify loci that were differentially methylated from baseline versus (vs.) each post-treatment timepoint across subjects. To identify loci whose methylation levels were modulated in relation to azacitidine PK parameters, Spearman's correlation coefficients were computed for azacitidine exposure (AUCinf) or peak plasma concentration (Cmax) vs. the fold change in methylation at Day 15 for each locus across subjects. To date, PK data have been generated for 31 of 45 enrolled subjects. Oral doses evaluated were 120, 180, 240, 300, 360, 480 and 600 mg. Following SC and oral administrations, azacitidine was rapidly absorbed and reached Cmax within 0.5 hr (0.2, 1.1) and 1.0 hr (0.5, 2.5) post-dose (median [min, max]), respectively. The concentration vs. time profiles declined in a pseudo bi-phasic manner, with a mean elimination half-life of 1.8 ± 1.1 hr and 0.74 ± 0.28 hr for SC and oral, respectively. For SC azacitidine, mean AUCinf = 1090 ± 470 hr*ng/mL, mean apparent total cleara