A Phase I Study in Patients with Solid or Hematologic Malignancies of the Dose Proportionality of Subcutaneous Azacitidine and Its Pharmacokinetics in Patients with Severe Renal Impairment

Laille, Eric; Goel, Sanjay; Mita, Alain C.; Gabrail, Nashat; Kelly, Kevin R.; Liu, Liangang; Songer, Stephen; Beach, C. L.

doi:10.1002/phar.1371

Cited by 15 publications

(21 citation statements)

References 12 publications

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“…A phase I study conducted in patients with both solid and hematologic malignancies revealed that azacitidine is dose proportional over the 25-100 mg/m 2 dosing range, and renal impairment had no important effect on azacitidine pharmacokinetics. Therefore, initial dose adjustments at the start of therapy in patients with renal impairment are not required [Laille et al 2014]. Patients with hepatic dysfunction should have frequent monitoring of their liver function tests and blood counts as they may also experience a greater incidence of hematologic side-effects.…”

Section: Safetymentioning

confidence: 99%

Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes

Navada

2016

Therapeutic Advances in Hematology

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Myelodysplastic syndromes (MDS) represent a clonal hematopoietic stem cell disorder characterized by morphologic features of dyspoiesis, a hyperproliferative bone marrow, and one or more peripheral blood cytopenias. In patients classified according to the Revised International Prognostic Scoring System (R-IPSS) with intermediate or higher-risk disease, there is an increased risk of death due to progressive bone marrow failure or transformation to acute myeloid leukemia (AML). Azacitidine was the first DNA hypomethylating agent approved by the United States (US) Food and Drug Administration (FDA) for the treatment of MDS and the only therapy that has demonstrated a significant survival benefit over conventional care regimens (CCRs) in patients with intermediate or higher-risk disease. Prolonged survival is independent of achieving a complete remission. Azacitidine has been used in older patients with both clinical and hematological improvement as well as an acceptable side effect profile. The most common adverse effect is myelosuppression. These findings support the use of azacitidine as an effective treatment in older patients with higher-risk MDS.

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Section: Safetymentioning

confidence: 99%

Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes

Navada

2016

Therapeutic Advances in Hematology

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“…Early clinical and pharmacological data in humans and animals suggested that AZA, particularly when used intravenously, may be potentially nephrotoxic 23‐25 and the prescribing information of the drug recommends close monitoring of renal function during 5‐AZA administration. However, others and we have shown that AZA therapy is feasible in patients with all stages of CKD and pharmacokinetics of AZA are not affected significantly by renal impairment 26,27 . Adverse events, response rates and survival in patients with mild and moderate CKD were comparable with the ones with normal renal function and only severe CKD appears to be associated with higher toxicity 28 …”

Section: Discussionmentioning

confidence: 76%

Estimated glomerular filtration rate independently predicts outcome of azacitidine therapy in higher‐risk Myelodysplastic syndromes. Results from 536 patients of the Hellenic National Registry of Myelodysplastic and Hypoplastic syndromes

Papadopoulos

Diamantopoulos

Papageorgiou

et al. 2020

Hematological Oncology

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Higher-risk Myelodysplastic syndromes (MDS) patients undergoing treatment with 5azacytidine (AZA) are typically elderly with several comorbidities. However, the effect of comorbidities on the effectiveness and safety of AZA in real-world settings remains unclear. We analyzed data from 536 AZA-treated patients with higher-risk MDS, Myelodysplastic/Myeloproliferative neoplasms and low blast count Acute Myeloid Leukemia enrolled to the Hellenic National Registry of Myelodysplastic and Hypoplastic Syndromes. Multivariate analysis adjusted also for the International Prog-Vasileios Papadopoulos and Panagiotis T. Diamantopoulos contributed equally to this study.

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“…In a study of patients with various tumor types who had renal impairment, azacitidine pharmacokinetics were unaffected (Laille et al, 2014). The SmPCs for both approved HMAs state that these drugs can be used in patients with renal impairment, and no specific modifications to the dose or frequency of administration are recommended (Dacogen SmPC; Vidaza SmPC).…”

Section: Special Populationsmentioning

confidence: 99%

Hypomethylating agents in the treatment of acute myeloid leukemia: A guide to optimal use

Ossenkoppele

2019

Critical Reviews in Oncology/Hematology

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The hypomethylating agents (HMAs), decitabine and azacitidine, are valuable treatment options in acute myeloid leukemia patients who are not eligible for intensive chemotherapy. Both agents are generally well tolerated, and complications most commonly relate to myelosuppression. Antibiotic / antifungal use, regular monitoring, and proactive patient education are important to minimize these events, and reduce the need for dose delay. Responses to HMAs are often not evident for up to 6 cycles, and there is currently no validated clinical marker for predicting response. Hence, treatment should be continued for at least 4-6 cycles to ensure that patients have sufficient opportunity to respond. Delivery of insufficient numbers of cycles is a key reason for HMA failure, and premature discontinuation must be avoided. Genetic factors offer potential for better predicting responders to HMAs in future, but require further study. continuing study drug (median OS: 12.1 vs 6.9 months; HR: 0.76; 95% CI: 0.60-0.96; p = 0.019) (Dombret et al., 2015).No randomized trial has ever directly compared decitabine and azacitidine in AML. Furthermore, indirect comparisons of the Phase 3 trials are complicated by important differences in the inclusion criteria,

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A Phase I Study in Patients with Solid or Hematologic Malignancies of the Dose Proportionality of Subcutaneous Azacitidine and Its Pharmacokinetics in Patients with Severe Renal Impairment

Abstract: Azacitidine is dose proportional over the 25-100 mg/m2 dosing range. Overall, renal impairment had no important effect on azacitidine PK. Therefore, no initial azacitidine dose adjustment in patients with renal impairment is required.

Cited by 15 publications

References 12 publications

Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes

Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes

Estimated glomerular filtration rate independently predicts outcome of azacitidine therapy in higher‐risk Myelodysplastic syndromes. Results from 536 patients of the Hellenic National Registry of Myelodysplastic and Hypoplastic syndromes

Hypomethylating agents in the treatment of acute myeloid leukemia: A guide to optimal use

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