5/14/2019
`
`Development of an Oral Dosage Form of Azacitidine: Overcoming Challenges in Chemistry, Formulation, and Bioavailability. | Blood Journal
`
` fl
`
`Advertisement
`
`Development of an Oral Dosage Form of Azacitidine: Overcoming Challenges in Chemistry,
`Formulation, and Bioavailability.
`Maxine L. Stoltz, Jeffrey B. Etter, Tanja Obradovic, and Richard Jia
`Blood 2006 108:4850;
`
`Info & Metrics
`
`Azacitidine (Vidaza®), an epigenetic modifier which exerts its therapeutic effect through gene demethylation, is currently approved in a
`subcutaneous (sc) dosage form for the treatment of myelodysplastic syndromes (MDS). Low-dose, chronic demethylation may lead to improved
`antiproliferative activity while minimizing side effects. Such chronic demethylation would require a convenient, more frequent dosing schedule. It
`has, therefore, been an objective of Pharmion Corporation to develop an oral dosage form of azacitidine that could improve the safety and efficacy
`attributes of the parenterally administered formulation plus have desirable pharmacokinetic characteristics. Azacitidine presents several significant
`challenges with respect to oral administration including sub-optimal physiochemical characteristics, hydrolytic instability, and active enzymatic
`degradation - all non-conducive to high passive intestinal tract absorption. Moreover, the drug requires formulated tablet strengths accommodating
`widely flexible treatment regimens yet must be formulated to avoid the chemical and enzymatic degradation occurring presystemically. Additionally,
`nonclinical testing of azacitidine bioavailability is hampered by inappropriate animal models representing human gastrointestinal tracts conditions,
`low tolerability of the drug in several animal species, widely variable pharmacokinetic behavior, and lack of highly sensitive bioanalytical methods for
`measuring the drug. Data on orally administered azacitidine are sparse but hint at some degree of bioavailability in mice where multiple oral dosing
`with the drug resulted in lower LD50 values than multiple dosing by the intravenous route (data on file at Pharmion). A published report following
`long term oral dosing (0.2 mg/kg/day of azacitidine plus 200 mg tetrahydrouridine 3 days per week) in a patient with sickle cell disease resulted in
`significant increases in total and fetal hemoglobin suggesting absorption of the drug followed by systemic effects (Dover, 1985). A study recently
`conducted in dogs given azacitidine orally (6 mg/kg) compared to sc and iv (2 mg/kg) showed the drug was absorbed rapidly by the oral route (T
`15 min) with absolute bioavailability of 67% (compared to 71% following sc dosing). Additional
`and
`characterization of azacitidine
`stability and permeability have been performed. Data from these studies have been utilized to develop a solid oral dosage form of azacitidine that
`will move forward into additional animal testing and clinical evaluation. Highly sensitive bioanalytical methods have also been developed for the
`quantitation of azacitidine in dog and human plasma. A single oral dose escalation study will be conducted in patients to assess the safety,
`tolerability, and pharmacokinetics of orally administered azacitidine. Data will be evaluated continuously during the dose escalation study.
`Information generated from these studies will be used to appropriately design a full oral azacitidine clinical development program.
`
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`,
`Pharmacokinetics of DFN-15, a novel oral solution of celecoxib, versus celecoxib
`400-mg capsules: A randomized crossover study in fasting healthy volunteers
`Remarq is the easiest way
`Pal A et al., MDLinx, 2017
`to take notes, share and
`
`follow articles
`high oral bioavailability in humans.
`D J Kempf et al., Proc Natl Acad Sci U S A, 1995
`
`ABT-538 is a potent inhibitor of human immunodeficiency virus protease and hase
`
`y d 5
`y d
`
`2006, The American Society of Hematology
`
`Potential Articles of Interest
`
`A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety,
`Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Patients with
`Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML).
`Guillermo Garcia-Manero et al., Blood, 2009
`
`Extended Dosing of Oral Azacitidine (CC-486) for 14 and 21 Days Provides More
`Effective Methylation Reversal Than a 7-Day Schedule
`
`http://www.bloodjournal.org/content/108/11/4850?sso-checked=true
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1034-0001
`
`
`
`Development of an Oral Dosage Form of Azacitidine: Overcoming Challenges in Chemistry, Formulation, and Bioavailability. | Blood Journal
`
` fl
`
`Advertisement
`
`Development of an Oral Dosage Form of Azacitidine: Overcoming Challenges in Chemistry,
`Formulation, and Bioavailability.
`Maxine L. Stoltz, Jeffrey B. Etter, Tanja Obradovic, and Richard Jia
`Blood 2006 108:4850;
`
`Info & Metrics
`
`Azacitidine (Vidaza®), an epigenetic modifier which exerts its therapeutic effect through gene demethylation, is currently approved in a
`subcutaneous (sc) dosage form for the treatment of myelodysplastic syndromes (MDS). Low-dose, chronic demethylation may lead to improved
`antiproliferative activity while minimizing side effects. Such chronic demethylation would require a convenient, more frequent dosing schedule. It
`has, therefore, been an objective of Pharmion Corporation to develop an oral dosage form of azacitidine that could improve the safety and efficacy
`attributes of the parenterally administered formulation plus have desirable pharmacokinetic characteristics. Azacitidine presents several significant
`challenges with respect to oral administration including sub-optimal physiochemical characteristics, hydrolytic instability, and active enzymatic
`degradation - all non-conducive to high passive intestinal tract absorption. Moreover, the drug requires formulated tablet strengths accommodating
`widely flexible treatment regimens yet must be formulated to avoid the chemical and enzymatic degradation occurring presystemically. Additionally,
`nonclinical testing of azacitidine bioavailability is hampered by inappropriate animal models representing human gastrointestinal tracts conditions,
`low tolerability of the drug in several animal species, widely variable pharmacokinetic behavior, and lack of highly sensitive bioanalytical methods for
`measuring the drug. Data on orally administered azacitidine are sparse but hint at some degree of bioavailability in mice where multiple oral dosing
`with the drug resulted in lower LD50 values than multiple dosing by the intravenous route (data on file at Pharmion). A published report following
`long term oral dosing (0.2 mg/kg/day of azacitidine plus 200 mg tetrahydrouridine 3 days per week) in a patient with sickle cell disease resulted in
`significant increases in total and fetal hemoglobin suggesting absorption of the drug followed by systemic effects (Dover, 1985). A study recently
`conducted in dogs given azacitidine orally (6 mg/kg) compared to sc and iv (2 mg/kg) showed the drug was absorbed rapidly by the oral route (T
`15 min) with absolute bioavailability of 67% (compared to 71% following sc dosing). Additional
`and
`characterization of azacitidine
`stability and permeability have been performed. Data from these studies have been utilized to develop a solid oral dosage form of azacitidine that
`will move forward into additional animal testing and clinical evaluation. Highly sensitive bioanalytical methods have also been developed for the
`quantitation of azacitidine in dog and human plasma. A single oral dose escalation study will be conducted in patients to assess the safety,
`tolerability, and pharmacokinetics of orally administered azacitidine. Data will be evaluated continuously during the dose escalation study.
`Information generated from these studies will be used to appropriately design a full oral azacitidine clinical development program.
`
`,
`max
`
`Take notes, share and follow articles, make comments, and collaborate with peers!
`
`DISCUSS
`
`ADD TO LIST
`
`FOLLOW
`
`SHARE
`
`COMMENT
`
`NOTE
`
`1/3
`
`,
`Pharmacokinetics of DFN-15, a novel oral solution of celecoxib, versus celecoxib
`400-mg capsules: A randomized crossover study in fasting healthy volunteers
`Remarq is the easiest way
`Pal A et al., MDLinx, 2017
`to take notes, share and
`
`follow articles
`high oral bioavailability in humans.
`D J Kempf et al., Proc Natl Acad Sci U S A, 1995
`
`ABT-538 is a potent inhibitor of human immunodeficiency virus protease and hase
`
`y d 5
`y d
`
`2006, The American Society of Hematology
`
`Potential Articles of Interest
`
`A Phase 1, Open-Label, Dose-Escalation Study to Evaluate the Safety,
`Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Patients with
`Myelodysplastic Syndromes (MDS) or Acute Myelogenous Leukemia (AML).
`Guillermo Garcia-Manero et al., Blood, 2009
`
`Extended Dosing of Oral Azacitidine (CC-486) for 14 and 21 Days Provides More
`Effective Methylation Reversal Than a 7-Day Schedule
`
`http://www.bloodjournal.org/content/108/11/4850?sso-checked=true
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1034-0001
`
`
`
`Development of an Oral Dosage Form of Azacitidine: Overcoming Challenges in Chemistry, Formulation, and Bioavailability. | Blood Journal
`5/14/2019
`Eric Laille et al., Blood, 2012
`Quantitative Analysis of Tozadenant Using Liquid Chromatography-Mass
`Spectrometric Method in Rat Plasma and Its Human Pharmacokinetics Prediction
`Using Physiologically Based Pharmacokinetic Modeling
`Lee et al., Molecules, 2019
`
`Phase I/II Study of MGCD0103, an Oral Isotype-Selective Histone Deacetylase
`(HDAC) Inhibitor, in Combination with 5-Azacitidine in Higher-Risk Myelodysplastic
`Syndrome (MDS) and Acute Myelogenous Leukemia (AML).
`Guillermo Garcia-Manero et al., Blood, 2007
`
`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.
`Kyle J MacBeth et al., Blood, 2009
`
`Phase 1 Assessment of an Orally Bioavailable Formulation of Gallium Nitrate
`(G4544).
`Thomas Julian et al., Blood, 2007
`
`Identification and Pharmacokinetic Studies on Complanatuside and Its Major
`Metabolites in Rats by UHPLC-Q-TOF-MS/MS and LC-MS/MS
`Yao, Yu-Feng et al., Molecules, 2018
`
`Development and Characterization of an Amorphous Solid Dispersion of
`Furosemide in the Form of a Sublingual Bioadhesive Film to Enhance Bioavailability
`
`De Caro et al., Pharmaceutics, 2017
`
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`http://www.bloodjournal.org/content/108/11/4850?sso-checked=true
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`2/3
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`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1034-0002
`
`
`
`Development of an Oral Dosage Form of Azacitidine: Overcoming Challenges in Chemistry, Formulation, and Bioavailability. | Blood Journal
`
`5/14/2019
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`http://www.bloodjournal.org/content/108/11/4850?sso-checked=true
`
`3/3
`
`Remarq is the easiest way
`to take notes, share and
`follow articles
`
`Apotex v. Cellgene - IPR2023-00512
`Petitioner Apotex Exhibit 1034-0003
`
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