https://ascopubs.orq/doi/abs/10.1200/jco.2007.25. 18 suppl.7084
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`Journal
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`A n American Society of Clinical Oncology Journal
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`LEUKEMIA, MYElODYSPLASii\, AND TRANSPLANTATION (ADULT)
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`An oral dosage formulation of azacitidine: A pilot
`pharmacokinetic study
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`Show More
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`Abstract
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`7084
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`Background: Azadtidine, a cytidine analog, ind uces DNA demethylation th at leads
`to tumor suppressor gene expression. Cellular effects of azadtidine treatment
`include d ifferentiation , cell cycle arrest and/o r apoptosis. There ls a complex, no n(cid:173)
`linear relationsh ip between plasma exposure and pharmacodynamic effect of
`azacltidine that can be fu lly explored wlth an oral formulation ofazacitidine,
`enabling a lternate dosing strategies ranging from intermittent hlgh dose to
`continuous, low-dose a ppm aches to DNA demethylation. Methods and Results: A
`pha rmacokinetic study in dogs given oral azacitidine demonstrated rapid
`absorption with abso lute bioava,lability of 67% {compared to 71 % following SC
`dosing). When comparing a single parenteral dose of 75 mg/m2 ( ~2 mg/ kg) given
`SC to humans vs. a single oral dose of 16 mg/m2 (0.8 mg/kg) given to dogs, plasma
`concentrations of a zacitidine were si milar despite the 4- to 5-fa ld difference in
`dose as calculated by body surface area (BSA). A 14-day toxico logy study in dogs
`evaluated the oral doses of 0.2, 0.4, and 0.8 mg/ kg/day. The high dose is the
`previous ly identified MTD of 0.55 mg/kg/day based on an oral bioavai!ability of
`67% (approximately equal to 16 mg/m'/day). Hematologk toxicity, a known and
`expected effect of azacitidine admin istered in a repeat-dose regimen was
`observed at the t wo highest doses. The oral MTD was determined to be 0.2
`mg/kg/day for 14 conserntive days followed by a 21-day recovery period. This
`provides a cumulative MTD of2.8 mg/kg for the14 day dosi ng regimen, which is
`similar to that seen with N dosing {2.75 mg/kg over 5 days). Based on t he
`pred!nic:al studies, a m uftiten ter, slngle-t reatme nt study of oral aza citi di ne is
`underway in subjects with MDS, AML, or solid tumorsc. The trial assesses the safety,
`tolerability and pharmacokinetics of escalating single doses of orally administered
`azacitidine. Clinical data from this study will be presented.
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`Author Disclosure
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`CELGENE 2040
`APOTEX v. CELGENE
`IPR2023-00512
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`1/1
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