AML, Hodgkin's Disease, MDS, Multiple Myeloma, Non-Hodgkin's Lymphoma, Solid Tumors
Conditions
Keywords
MDS, AML, Solid Tumors, Azacitidine, PK, Pharmacokinetics, Renal Impairment, Multiple Myeloma, Non-Hodgkin's Lymphoma, Hodgkin's Disease
Brief summary
The purpose of this study is to evaluate three things. The first being whether azacitidine is absorbed in the body at the same rate or proportion for different concentrations. The second is to determine the effect renal impairment has or does not have on the absorption of azacitidine. The third is to determine if azacitidine is safe and well tolerated in patients with renal function impairment.
Interventions
DRUGazacitidine
Sponsors
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of one of the following: * MDS according to the French-American-British (FAB) classification system: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), or chronic myelomonocytic leukemia (CMML); or * Acute myelogenous leukemia (AML) in remission, * Malignant solid tumor, * Multiple myeloma (MM), * Non-Hodgkin lymphoma (NHL), or * Hodgkin lymphoma (HD) * Patients with a history of treated brain metastases should be clinically stable for greater than 4 weeks prior to signing the informed consent form and off glucocorticoid therapy for central nervous system (CNS) edema for at least 4 weeks * Be capable of giving informed consent * Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 * Have a life expectancy ≥ 3 months * Have stable renal function for at least 2 months * Have average calculated creatinine clearance of: * \>80 mL/min/1.73m\^2 for Cohorts 1, 2, 3, and 4 * \<30 mL/min/1.73m\^2 for Cohort 5 - Severe renal impairment, * 50-80 mL/min/1.73m\^2 for Cohort 6 - Mild renal impairment, * 30 to \<50 mL/min/1.73m\^2 for Cohort 7 - Moderate renal impairment * Have organ and marrow function at the screening and pre-dose visits as defined below: * Hemoglobin ≥8 g/dL, * Absolute neutrophil count ≥0.75 x 10\^3/µL, * Platelets ≥30 x 10\^3/µL, * Total bilirubin ≤1.5 times the upper limit of normal (ULN), * Aspartate aminotransferase (AST) ≤2 times the ULN, and * Alanine transaminase (ALT) ≤2 times the ULN; * Have a 12-lead electrocardiogram (ECG) that is not clinically significant, as determined by the Investigator, at screening * Have serum bicarbonate: * 20 mEq/L for patients with normal renal function (cohorts 1, 2, 3 and 4), * 16 mEq/L for patients with impaired renal function (cohorts 5, 6 and 7) * Women of childbearing potential may participate, providing are not pregnant and agree to use at least 2 effective contraceptive methods throughout the study * Males with a female partner of childbearing potential must agree to use at least 2 effective contraceptive methods throughout the study and to avoid fathering a child for 6 months following the date of the last dose of study medication * Be a nonsmoker or must not have smoked for at least 30 days before the screening visit and agree to abstain from smoking during study participation
Exclusion criteria
* Women who are pregnant or nursing; * Had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to signing informed consent * Have been treated with an investigational agent within 4 weeks prior to signing the informed consent form * Have ongoing clinically significant adverse event(s) due to chemotherapy, radiotherapy or investigational agents administered more than 4 weeks prior to signing the informed consent as determined by the Investigator * Have known or suspected hypersensitivity to azacitidine or mannitol * Have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia * Have low blood pressure (supine blood pressure \<90/60 mmHg) * Have human immunodeficiency virus (HIV), or active hepatitis virus B or C * Have advanced malignant hepatic tumors * Have end stage renal disease requiring dialysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule. |
| Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule. |
| Area Under the Plasma Concentration-time Curve From Time Zero to Infinity | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine after a single dose, calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant. |
| Maximum Plasma Concentration of Azacitidine (Cmax) | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The maximum observed plasma concentration of azacitidine after a single dose on Day 1. |
| Time to Maximum Plasma Concentration of Azacitidine (Tmax) | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1. |
| Terminal Phase Half-life of Azacitidine (t½) | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The terminal phase half-life of azacitidine after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant. |
| Apparent Total Clearance of Azacitidine (CL/F) | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf. |
| Apparent Volume of Distribution of Azacitidine (Vz/F) | Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The apparent volume of distribution of azacitidine after a single dose on Day 1, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz) |
| Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The effect of renal impairment on azacitidine pharmacokinetics was analyzed by comparing PK parameters obtained on Days 1 and 5 from participants with severe renal impairment and those with normal renal function. Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule. |
| Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule for participants with normal renal function and for participants with severe renal impairment. |
| Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine, after a single dose (Day 1) and multiple doses (Day 5), calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant. |
| Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and for participants with severe renal impairment. |
| Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The time to first maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment. |
| Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The terminal phase half-life of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant. |
| Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The apparent total clearance of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated as Dose/AUC0-inf. |
| Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine | Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose | The apparent volume of distribution of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz). |
| Number of Participants With Adverse Events (AEs) | Initial treatment phase: Days 1-11 for participants who received a single dose; Days 1-29 for participants who received multiple doses. Extension treatment period: From the date of first dose until 28 days after the date of last dose (up to 7 months). | A serious adverse event is one that at any dose of the study drug or at any time during the period of observation: * Results in death; * Is life threatening; * Requires inpatient hospitalization or prolongation of existing hospitalization; * Results in persistent or significant disability/incapacity; * Is a congenital anomaly/birth defect; * Is medically important. The Investigator assessed each AE for potential causal relationship between the event and study drug. The intensity of adverse changes in physical signs or symptoms was graded from 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Azacitidine 25 mg/m^2 Participants with normal renal function (defined as creatinine clearance \> 80 mL/min/1.73m\^2) received a single subcutaneous dose of azacitidine 25 mg/m\^2 on Day 1. | 5 |
| Azacitidine 50 mg/m^2 Participants with normal renal function received a single subcutaneous dose of azacitidine 50 mg/m\^2 on Day 1. | 5 |
| Azacitidine 75 mg/m^2 Participants with normal renal function received subcutaneous doses of azacitidine 75 mg/m\^2 on Days 1 to 5. | 6 |
| Azacitidine 100 mg/m^2 Participants with normal renal function received a single subcutaneous dose of azacitidine 100 mg/m\^2 on Day 1. | 5 |
| Severe RI: Azacitidine 75 mg/m^2 Participants with severe renal impairment (RI; defined as creatinine clearance \< 30 mL/min/1.73 m\^2) received subcutaneous doses of azacitidine 75 mg/m\^2 on Days 1 to 5. | 6 |
| Extension Phase: Normal RF Participants with normal renal function (RF) received up to 6 cycles of treatment with 75 mg/m\^2 azacitidine daily on Days 1-7 of each 28-day cycle. | 14 |
| Extension Phase: Severe RI Participants with severe renal impairment (RI) received up to 6 cycles of treatment with 75 mg/m\^2 azacitidine daily on Days 1-7 of each 28-day cycle. | 4 |
| Total | 45 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Extension Phase | Adverse Event | 0 | 0 | 0 | 0 | 0 | 2 | 1 |
| Extension Phase | Death | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Extension Phase | No Longer Receiving Clinical Benefit | 0 | 0 | 0 | 0 | 0 | 6 | 0 |
| Extension Phase | Physician Decision | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Extension Phase | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 2 | 0 |
| Initial Treatment Phase | Adverse Event | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Initial Treatment Phase | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Initial Treatment Phase | Physician Decision | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Initial Treatment Phase | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Initial Treatment Phase | Sponsor Request | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Azacitidine 25 mg/m^2 | Azacitidine 50 mg/m^2 | Azacitidine 75 mg/m^2 | Azacitidine 100 mg/m^2 | Severe RI: Azacitidine 75 mg/m^2 | Extension Phase: Normal RF | Extension Phase: Severe RI |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous Extension Treatment Period | 62.4 years STANDARD_DEVIATION 10.15 | NA years | NA years | NA years | NA years | NA years | 60.6 years STANDARD_DEVIATION 9.52 | 68.8 years STANDARD_DEVIATION 11 |
| Age, Continuous Initial Treatment Period | 63.5 years STANDARD_DEVIATION 12.32 | 67.6 years STANDARD_DEVIATION 3.78 | 64.6 years STANDARD_DEVIATION 9.63 | 53.5 years STANDARD_DEVIATION 10.19 | 57.0 years STANDARD_DEVIATION 12.02 | 74.5 years STANDARD_DEVIATION 12.58 | NA years | NA years |
| Body Surface Area (BSA) Extension Period | 1.9 m^2 STANDARD_DEVIATION 0.31 | NA m^2 | NA m^2 | NA m^2 | NA m^2 | NA m^2 | 1.9 m^2 STANDARD_DEVIATION 0.35 | 1.9 m^2 STANDARD_DEVIATION 0.06 |
| Body Surface Area (BSA) Initial Treatment Period | 1.9 m^2 STANDARD_DEVIATION 0.27 | 2.0 m^2 STANDARD_DEVIATION 0.2 | 1.9 m^2 STANDARD_DEVIATION 0.28 | 1.9 m^2 STANDARD_DEVIATION 0.42 | 1.6 m^2 STANDARD_DEVIATION 0.15 | 1.8 m^2 STANDARD_DEVIATION 0.15 | NA m^2 | NA m^2 |
| Cancer Diagnosis: Extension Phase Chronic myelomonocytic leukemia | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Cancer Diagnosis: Extension Phase Multiple myeloma | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Cancer Diagnosis: Extension Phase Myelodysplastic syndrome-RA | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Cancer Diagnosis: Extension Phase Myelodysplastic syndrome-RAEB-T | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Cancer Diagnosis: Extension Phase Myelodysplastic syndrome-RARS | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Cancer Diagnosis: Extension Phase Solid tumor | 15 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 12 participants | 3 participants |
| Cancer Diagnosis: Initial Treatment Phase Chronic myelomonocytic leukemia | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Cancer Diagnosis: Initial Treatment Phase Multiple myeloma | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Cancer Diagnosis: Initial Treatment Phase Myelodysplastic syndrome-RA | 2 participants | 0 participants | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Cancer Diagnosis: Initial Treatment Phase Myelodysplastic syndrome-RAEB-T | 2 participants | 1 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Cancer Diagnosis: Initial Treatment Phase Myelodysplastic syndrome-RARS | 1 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Cancer Diagnosis: Initial Treatment Phase Solid tumor | 20 participants | 3 participants | 3 participants | 5 participants | 5 participants | 4 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status: Extension Phase 0 | 3 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants | 1 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status: Extension Phase 1 | 14 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 11 participants | 3 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status: Extension Phase 2 | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status: Initial Treatment Phase 0 | 7 participants | 2 participants | 2 participants | 1 participants | 0 participants | 2 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status: Initial Treatment Phase 1 | 18 participants | 3 participants | 3 participants | 4 participants | 5 participants | 3 participants | 0 participants | 0 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status: Initial Treatment Phase 2 | 2 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants |
| Gender of Extension Period Participants Female | 10 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 8 participants | 2 participants |
| Gender of Extension Period Participants Male | 8 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 6 participants | 2 participants |
| Race/Ethnicity, Customized Black | 8 participants | 1 participants | 2 participants | 1 participants | 2 participants | 2 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 19 participants | 4 participants | 3 participants | 5 participants | 3 participants | 4 participants | 0 participants | 0 participants |
| Race: Extension Phase Black | 5 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 5 participants | 0 participants |
| Race: Extension Phase White | 13 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 9 participants | 4 participants |
| Region of Enrollment United States | 27 participants | 5 participants | 5 participants | 6 participants | 5 participants | 6 participants | 0 participants | 0 participants |
| Sex/Gender, Customized Female | 16 participants | 3 participants | 3 participants | 3 participants | 4 participants | 3 participants | 0 participants | 0 participants |
| Sex/Gender, Customized Male | 11 participants | 2 participants | 2 participants | 3 participants | 1 participants | 3 participants | 0 participants | 0 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 5 | 3 / 5 | 5 / 6 | 5 / 5 | 6 / 6 | 9 / 14 | 4 / 4 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 4 / 6 | 1 / 5 | 1 / 6 | 8 / 14 | 3 / 4 |
Outcome results
Primary
Apparent Total Clearance of Azacitidine (CL/F)
The apparent total clearance of azacitidine after a single dose on Day 1, calculated as Dose/AUC0-inf.
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) | 104.58 liters/hour | Geometric Coefficient of Variation 25 |
| Azacitidine 50 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) | 105.76 liters/hour | Geometric Coefficient of Variation 17.03 |
| Azacitidine 75 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) | 151.55 liters/hour | Geometric Coefficient of Variation 30.88 |
| Azacitidine 100 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) | 106.00 liters/hour | Geometric Coefficient of Variation 25.64 |
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance model on the nature log-transformed CL/F obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.90% CI: [71.2, 143.6]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance model on the nature log-transformed CL/F obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.90% CI: [103.6, 202.7]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance model on the nature log-transformed CL/F obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.90% CI: [71.4, 143.9]
Primary
Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine
The apparent total clearance of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated as Dose/AUC0-inf.
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 25 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine | Day 5 | 166.95 liters/hour | Geometric Coefficient of Variation 27.59 |
| Azacitidine 25 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine | Day 1 | 151.55 liters/hour | Geometric Coefficient of Variation 30.88 |
| Azacitidine 50 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine | Day 1 | 85.76 liters/hour | Geometric Coefficient of Variation 68.83 |
| Azacitidine 50 mg/m^2 | Apparent Total Clearance of Azacitidine (CL/F) After Single and Multiple Doses of Azacitidine | Day 5 | 111.55 liters/hour | Geometric Coefficient of Variation 51.75 |
Primary
Apparent Volume of Distribution of Azacitidine (Vz/F)
The apparent volume of distribution of azacitidine after a single dose on Day 1, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz)
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) | 208.69 liters | Geometric Coefficient of Variation 45.57 |
| Azacitidine 50 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) | 96.74 liters | Geometric Coefficient of Variation 36.75 |
| Azacitidine 75 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) | 259.44 liters | Geometric Coefficient of Variation 121.71 |
| Azacitidine 100 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) | 456.69 liters | Geometric Coefficient of Variation 99.41 |
Primary
Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine
The apparent volume of distribution of azacitidine after a single dose (Day 1) and multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the equation: Vz/F = Apparent total clearance (CL/F) / terminal phase rate constant (λz).
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 25 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine | Day 5 | 248.57 liters | Geometric Coefficient of Variation 115.1 |
| Azacitidine 25 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine | Day 1 | 259.44 liters | Geometric Coefficient of Variation 121.71 |
| Azacitidine 50 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine | Day 1 | 120.47 liters | Geometric Coefficient of Variation 120.45 |
| Azacitidine 50 mg/m^2 | Apparent Volume of Distribution of Azacitidine (Vz/F) After Single and Multiple Doses of Azacitidine | Day 5 | 184.54 liters | Geometric Coefficient of Variation 104.34 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose
Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic (PK) Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose | 455.86 ng*hr/mL | Geometric Coefficient of Variation 26.04 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose | 897.43 ng*hr/mL | Geometric Coefficient of Variation 31 |
| Azacitidine 75 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose | 921.87 ng*hr/mL | Geometric Coefficient of Variation 39.215 |
| Azacitidine 100 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose | 1502.86 ng*hr/mL | Geometric Coefficient of Variation 25.57 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine
The effect of renal impairment on azacitidine pharmacokinetics was analyzed by comparing PK parameters obtained on Days 1 and 5 from participants with severe renal impairment and those with normal renal function. Area under the plasma concentration-time curve from time 0 to 8 hours post-dose (AUC0-8) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule.
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine | Day 5 | 843.03 ng*hr/mL | Geometric Coefficient of Variation 12 |
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine | Day 1 | 921.87 ng*hr/mL | Geometric Coefficient of Variation 39.15 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine | Day 1 | 1558.32 ng*hr/mL | Geometric Coefficient of Variation 64.95 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to 8 Hours Post-dose After Single and Multiple Doses of Azacitidine | Day 5 | 1183.61 ng*hr/mL | Geometric Coefficient of Variation 51.92 |
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine
The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine, after a single dose (Day 1) and multiple doses (Day 5), calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine | Day 1 | 946.22 ng*hr/mL | Geometric Coefficient of Variation 39.05 |
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine | Day 5 | 857.64 ng*hr/mL | Geometric Coefficient of Variation 9.94 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine | Day 1 | 1573.82 ng*hr/mL | Geometric Coefficient of Variation 63.46 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to Infinity After Single and Multiple Doses of Azacitidine | Day 5 | 1210.92 ng*hr/mL | Geometric Coefficient of Variation 49.07 |
Comparison: Comparison of AUC0-inf after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.~Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.90% CI: [108.6, 254.6]
Comparison: Comparison of AUC0-inf after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.~Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.90% CI: [92.2, 216.2]
Primary
Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine
The area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose (Day 1) and multiple doses (Day 5) was calculated by the linear trapezoidal rule for participants with normal renal function and for participants with severe renal impairment.
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine | Day 1 | 920.76 ng*hr/mL | Geometric Coefficient of Variation 39.2 |
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine | Day 5 | 841.62 ng*hr/mL | Geometric Coefficient of Variation 11.83 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine | Day 1 | 1558.72 ng*hr/mL | Geometric Coefficient of Variation 65.02 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time 0 to the Last Quantifiable Time Point After Single and Multiple Doses of Azacitidine | Day 5 | 1181.83 ng*hr/mL | Geometric Coefficient of Variation 51.98 |
Comparison: Comparison of AUC0-t after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.~Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters90% CI: [109.2, 262.5]
Comparison: Comparison of AUC0-t after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.~Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.90% CI: [90.6, 217.7]
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity
The area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) for azacitidine after a single dose, calculated by the linear trapezoidal rule and extrapolated to infinity according to the following equation: AUC0-inf = AUC0-t + (Ct/ke), where Ct is the last quantifiable concentration and ke = elimination rate constant.
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity | 460.47 ng*hr/mL | Geometric Coefficient of Variation 25.79 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity | 897.42 ng*hr/mL | Geometric Coefficient of Variation 30.93 |
| Azacitidine 75 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity | 945.50 ng*hr/mL | Geometric Coefficient of Variation 39.05 |
| Azacitidine 100 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to Infinity | 1533.37 ng*hr/mL | Geometric Coefficient of Variation 23.96 |
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-inf, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.90% CI: [63.8, 148.8]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-inf, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.90% CI: [45.7, 102.7]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-inf, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons.90% CI: [54.5, 127.1]
Primary
Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point
Area under the plasma concentration-time curve from time zero to the last quantifiable time point (AUC0-t) of azacitidine following a single dose of azacitidine on Day 1, calculated by the linear trapezoidal rule.
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point | 454.80 ng*hr/mL | Geometric Coefficient of Variation 26.22 |
| Azacitidine 50 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point | 895.38 ng*hr/mL | Geometric Coefficient of Variation 31.2 |
| Azacitidine 75 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point | 920.76 ng*hr/mL | Geometric Coefficient of Variation 39.2 |
| Azacitidine 100 mg/m^2 | Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Time Point | 1505.16 ng*hr/mL | Geometric Coefficient of Variation 25.57 |
Comparison: Geometric means, ratio and 90% confidence interval (CI) of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons90% CI: [64, 151.3]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons90% CI: [44.7, 101.8]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized AUC0-t, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons90% CI: [53.8, 127.2]
Primary
Maximum Plasma Concentration of Azacitidine (Cmax)
The maximum observed plasma concentration of azacitidine after a single dose on Day 1.
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) | 293.38 ng/mL | Geometric Coefficient of Variation 34.11 |
| Azacitidine 50 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) | 749.04 ng/mL | Geometric Coefficient of Variation 61.03 |
| Azacitidine 75 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) | 745.50 ng/mL | Geometric Coefficient of Variation 57.9 |
| Azacitidine 100 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) | 1261.96 ng/mL | Geometric Coefficient of Variation 39.19 |
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized Cmax, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons90% CI: [66.3, 245.7]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized Cmax, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons90% CI: [45.3, 158.5]
Comparison: Geometric means, ratio and 90% CI of ratio of geometric means are from one way analysis of variance models on the nature log-transformed dose-normalized Cmax, obtained on Day 1. Azacitidine 25 mg/m\^2 is the reference group for comparisons90% CI: [55.9, 207]
Primary
Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine
The maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and for participants with severe renal impairment.
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 25 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine | Day 1 | 745.50 ng/mL | Geometric Coefficient of Variation 57.9 |
| Azacitidine 25 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine | Day 5 | 632.56 ng/mL | Geometric Coefficient of Variation 45.86 |
| Azacitidine 50 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine | Day 1 | 1056.66 ng/mL | Geometric Coefficient of Variation 93.01 |
| Azacitidine 50 mg/m^2 | Maximum Plasma Concentration of Azacitidine (Cmax) After Single and Multiple Doses of Azacitidine | Day 5 | 668.11 ng/mL | Geometric Coefficient of Variation 91.64 |
Comparison: Comparison of Cmax after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.~Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.90% CI: [73.2, 274.6]
Comparison: Comparison of Cmax after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.~Geometric means, ratio and 90% CI of ratio of geometric means are from an analysis of variance model with renal function group (normal and severe), visit (Day 1 and Day 5), renal function group by visit interaction as fixed effect, and patient nested within renal function group as a random effect on the nature log-transformed pharmacokinetic parameters.90% CI: [54.5, 204.6]
Primary
Number of Participants With Adverse Events (AEs)
A serious adverse event is one that at any dose of the study drug or at any time during the period of observation: * Results in death; * Is life threatening; * Requires inpatient hospitalization or prolongation of existing hospitalization; * Results in persistent or significant disability/incapacity; * Is a congenital anomaly/birth defect; * Is medically important. The Investigator assessed each AE for potential causal relationship between the event and study drug. The intensity of adverse changes in physical signs or symptoms was graded from 1 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3, and according to the following: Mild (Grade 1), Moderate (Grade 2), Severe (Grade 3), Life threatening (Grade 4), or Death (Grade 5).
Time frame: Initial treatment phase: Days 1-11 for participants who received a single dose; Days 1-29 for participants who received multiple doses. Extension treatment period: From the date of first dose until 28 days after the date of last dose (up to 7 months).
Population: Safety population, all enrolled patients who received at least one dose of azacitidine and who had at least one post-treatment safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | Any adverse event | 4 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug interruption | 0 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event related to study drug | 0 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | Grade 3 or 4 adverse event | 0 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to other action taken | 2 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to a dose reduction | 0 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 0 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug discontinuation | 0 participants |
| Azacitidine 25 mg/m^2 | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 2 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 0 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | Any adverse event | 3 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 3 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to other action taken | 1 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug discontinuation | 0 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug interruption | 0 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event related to study drug | 0 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | Grade 3 or 4 adverse event | 0 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to a dose reduction | 0 participants |
| Azacitidine 50 mg/m^2 | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to other action taken | 6 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event related to study drug | 0 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 4 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Grade 3 or 4 adverse event | 4 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug discontinuation | 0 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 4 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug interruption | 0 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Any adverse event | 6 participants |
| Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to a dose reduction | 0 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug discontinuation | 0 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | Any adverse event | 5 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | Grade 3 or 4 adverse event | 1 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 1 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to other action taken | 4 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to a dose reduction | 0 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event related to study drug | 1 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug interruption | 0 participants |
| Azacitidine 100 mg/m^2 | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 4 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event related to study drug | 0 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Serious adverse event | 1 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Grade 3 or 4 adverse event | 3 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug discontinuation | 0 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to study drug interruption | 0 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to a dose reduction | 0 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Any adverse event | 6 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 3 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | Death | 0 participants |
| Severe RI: Azacitidine 75 mg/m^2 | Number of Participants With Adverse Events (AEs) | AE leading to other action taken | 5 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 8 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | AE leading to study drug discontinuation | 4 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | AE leading to a dose reduction | 1 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | AE leading to study drug interruption | 4 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | Death | 1 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | AE leading to other action taken | 10 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | Grade 3 or 4 adverse event | 10 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | Serious adverse event related to study drug | 1 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | Any adverse event | 14 participants |
| Extension Phase: Normal RF | Number of Participants With Adverse Events (AEs) | Serious adverse event | 8 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | Any adverse event | 4 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | AE leading to study drug discontinuation | 2 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | Serious adverse event | 3 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 2 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | Grade 3 or 4 adverse event | 3 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | Serious adverse event related to study drug | 1 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | AE leading to other action taken | 3 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | AE leading to a dose reduction | 0 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | Death | 1 participants |
| Extension Phase: Severe RI | Number of Participants With Adverse Events (AEs) | AE leading to study drug interruption | 1 participants |
Primary
Terminal Phase Half-life of Azacitidine (t½)
The terminal phase half-life of azacitidine after a single dose on Day 1, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) | 1.38 hours | Geometric Coefficient of Variation 27.31 |
| Azacitidine 50 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) | 0.63 hours | Geometric Coefficient of Variation 35.72 |
| Azacitidine 75 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) | 1.19 hours | Geometric Coefficient of Variation 102.56 |
| Azacitidine 100 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) | 1.03 hours | Geometric Coefficient of Variation 78.48 |
Primary
Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine
The terminal phase half-life of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment, calculated according to the following equation: t½ = 0.693/λz, where λz is the terminal phase rate constant.
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Azacitidine 25 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine | Day 1 | 1.19 hours | Geometric Coefficient of Variation 102.56 |
| Azacitidine 25 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine | Day 5 | 1.03 hours | Geometric Coefficient of Variation 76.95 |
| Azacitidine 50 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine | Day 5 | 1.15 hours | Geometric Coefficient of Variation 53.86 |
| Azacitidine 50 mg/m^2 | Terminal Phase Half-life of Azacitidine (t½) After Single and Multiple Doses of Azacitidine | Day 1 | 0.97 hours | Geometric Coefficient of Variation 43.88 |
Primary
Time to Maximum Plasma Concentration of Azacitidine (Tmax)
The time to first maximum observed plasma concentration of azacitidine after a single dose on Day 1.
Time frame: Day 1 at predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants with normal renal function only.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Azacitidine 25 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) | 0.25 hours |
| Azacitidine 50 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) | 0.25 hours |
| Azacitidine 75 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) | 0.25 hours |
| Azacitidine 100 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) | 0.27 hours |
Primary
Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine
The time to first maximum observed plasma concentration of azacitidine after a single dose (Day 1) or multiple doses (Day 5) for participants with normal renal function and severe renal impairment.
Time frame: Day 1 and Day 5: predose, 5, 15, 30, 45 minutes and 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8 hours post-dose
Population: Pharmacokinetic Population, consisting of all participants with evaluable plasma or urine concentration data for azacitidine. This analysis was performed for participants in the 2 treatment groups who received azacitidine treatment for 5 days.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Azacitidine 25 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine | Day 1 | 0.25 hours |
| Azacitidine 25 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine | Day 5 | 0.38 hours |
| Azacitidine 50 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine | Day 1 | 0.50 hours |
| Azacitidine 50 mg/m^2 | Time to Maximum Plasma Concentration of Azacitidine (Tmax) After Single and Multiple Doses of Azacitidine | Day 5 | 0.64 hours |
Comparison: Comparison of Tmax after a single dose (Day 1) in participants with normal renal function and participants with severe renal impairment.p-value: 0.134290% CI: [0, 0.52]Wilcoxon (Mann-Whitney)
Comparison: Comparison of Tmax after multiple doses (Day 5) in participants with normal renal function and participants with severe renal impairment.p-value: 0.101790% CI: [0, 0.5]Wilcoxon (Mann-Whitney)