A pilot pharmacokinetic study of oral azacitidine

Garcia‐Manero, Guillermo; Stoltz, M.; Ward, M. Renee; Kantarjian, Hagop M.; Sharma, Shilpy

doi:10.1038/leu.2008.145

Cited by 66 publications

(47 citation statements)

References 22 publications

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“…The effect of different dosing schedules, doses, duration of therapy, route of administration, [44][45][46] and combinations of azacitidine with other agents 47 also should be investigated further in this important subset of patients with MDS.…”

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confidence: 99%

Azacitidine for the treatment of lower risk myelodysplastic syndromes

Musto

Maurillo

Spagnoli

et al. 2010

Cancer

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BACKGROUND:Azacitidine induces responses and prolongs overall survival compared with conventional care regimens in patients who have high‐risk myelodysplastic syndromes (MDS). However, limited data are available concerning the efficacy and safety of azacitidine in patients who have lower risk MDS.METHODS:The authors retrospectively evaluated 74 patients with International Prognostic Scoring System low‐risk or intermediate 1‐risk MDS, who received azacitidine on a national named patient program. At baseline, 84% of patients were transfusion‐dependent, 57% had received erythropoietin, and 51% were aged >70 years. Azacitidine was administered subcutaneously for 5 days (n = 29 patients), 7 days (n = 43 patients), or 10 days (n = 2 patients) every month at a dose of 75 mg/m2 daily (n = 45 patients) or at a fixed dose of 100 mg daily (n = 29 patients) and for a median of 7 cycles (range, 1‐30 cycles).RESULTS:According to the 2006 International Working Group criteria, overall response rate (ORR) was 45.9%, including complete responses (10.8%), partial responses (9.5%), hematologic improvements (20.3%), and bone marrow complete responses (5.4%). The ORR was 51.6% in 64 patients who completed ≥4 cycles of treatment. The median duration of response was 6 months (range, 1‐30 months). After a median follow‐up of 15 months, 71% of patients remained alive. A survival benefit was observed in responders versus nonresponders (94% vs 54% of patients projected to be alive at 2.5 years, respectively; P < .0014). The most common grade 3 or 4 adverse events were myelosuppression (21.6%) and infection (6.8%).CONCLUSIONS:The current results indicated that azacitidine may be a feasible and effective treatment for patients with lower risk MDS. Cancer 2010. © 2010 American Cancer Society.

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confidence: 99%

Azacitidine for the treatment of lower risk myelodysplastic syndromes

Musto

Maurillo

Spagnoli

et al. 2010

Cancer

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“…All four patients had measurable plasma concentrations, allowing for comparison with historical s.c. azacitidine PK data. The 80-mg oral azacitidine dose had mean bioavailability of 17% of that of s.c. azacitidine [56,65]. No severe drug-related toxicities were observed, and results from this pilot study led to the development of a phase I study of oral azacitidine.…”

Section: Pilot Study Of Oral Azacitidinementioning

confidence: 99%

“…Oral administration of azacitidine avoids injection-site reactions and may enhance patient convenience compared with an injectable formulation [56,57]. It allows for the evaluation of alternative doses and schedules, including extended dosing schedules.…”

Section: Rationale For Oral Administration Of Azacitidinementioning

confidence: 99%

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Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

Cogle

Scott

Boyd³

2015

The Oncologist

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The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal myeloid malignancies characterized by multilineage cytopenias, recurrent cytogenetic abnormalities, and risk of progression to acute myeloid leukemia (AML). AML, which can occur de novo as well as secondary to MDS, is characterized by malignant clones of myeloid lineage in the bone marrow and peripheral blood, with dissemination into tissues. The cytidine nucleoside analog and epigenetic modifier azacitidine is approved in the U.S. for the treatment of all French-American-British subtypes of MDS and in many countries for the treatment of AML with 20%-30% blasts and multilineage dysplasia according to the World Health Organization classification. Benefits of azacitidine treatment of patients with AML with .30% blasts have also been shown in a recent phase III trial. Oral administration of azacitidine may enhance patient convenience, eliminate injection-site reactions, allow for alternative dosing and scheduling, and enable long-term treatment. Phase I studies with oral azacitidine (CC-486) have shown biological activity, clinical responses, and tolerability in patients with MDS and AML. Extended dosing schedules of oral azacitidine (for 14 or 21 days of 28-day cycles) are currently under investigation as frontline therapy in patients with lower risk MDS, as maintenance therapy for patients with AML not eligible for stem cell transplant, and as maintenance therapy for patients with MDS or AML following stem cell transplant. This review presents clinical data supporting the use of injectable azacitidine in MDS and AML and examines the rationale for and results of the clinical development of oral azacitidine.

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“…The combined therapy was generally well tolerated and resulted in a CR/CRi rate of 44 % in elderly AML patients and is now under investigation in further trials [22]. The development of an oral azacitidine formulation raises the possibility of an outpatient oral regimen for patients with AML who are not candidates for intensive chemotherapy [23]. Oral azacitidine was tested in myelodysplastic syndrome, chronic myelomonocytic leukemia as well as AML and based on promoter methylation status, oral administration was found to have slightly attenuated but similar biological activity when compared to parenteral azacitidine.…”

Section: Epigenetic Modulatorsmentioning

confidence: 99%

Novel agents in acute myeloid leukemia

Ungewickell

Medeiros

2012

Int J Hematol

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Although complete remissions can be achieved in most patients younger than 60 years of age with untreated acute myeloid leukemia (AML), only 30-40 % of patients remain long-term survivors. Furthermore, longterm survivors represent only 10-15 % of all AML patients older than 60 years of age and \10 % of all patients with relapsed AML. The development of new treatments for AML is therefore needed. Novel therapies should target specific mechanisms and pathways implicated in the development and maintenance of AML, should strive to have better tolerability than conventional combination chemotherapy, be associated with improved quality of life and minimize utilization of health care resources. In this manuscript, we discuss the role of epigenetic regulators and immunomodulatory agents in the treatment of AML. Also, we review the data on inhibitors of protein homeostasis and its synergistic effect to DNA methyltransferase inhibitors, the potential role for inhibitors of heat shock proteins and the mitotic machinery and a novel formulation of conventional chemotherapeutic agents given at a fixed molar concentration. Finally, we briefly share our views on optimal clinical trial design and patient selection for future studies in AML.

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A pilot pharmacokinetic study of oral azacitidine

Cited by 66 publications

References 22 publications

Azacitidine for the treatment of lower risk myelodysplastic syndromes

Azacitidine for the treatment of lower risk myelodysplastic syndromes

Oral Azacitidine (CC-486) for the Treatment of Myelodysplastic Syndromes and Acute Myeloid Leukemia

Novel agents in acute myeloid leukemia

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