Renal Impairment
Conditions
Keywords
AMD3100
Brief summary
Eligible male and female subjects with renal impairment (aged 18-78 years) and healthy control subjects (aged 35 to 78 years) will be enrolled in the study. Subjects with renal impairment will be enrolled and entered into three groups based on their renal function: Mild Impairment, Moderate Impairment, and Severe Impairment(not requiring dialysis). Control subjects will have normal renal function. The screening visits will occur within 14 days prior to plerixafor administration on study day one. Subjects will be monitored for 10 hours following administration of the study drug. In addition, subjects will return to the clinic at 24 and 48 hours after plerixafor administration for blood samples and safety assessments.
Detailed description
This is a phase I, open label, multi-center study in which up to eighteen subjects with renal impairment and six healthy control subjects with normal renal function will receive a single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. Eligible male and female subjects with renal impairment (aged 18-78 years) and healthy control subjects (aged in the upper age range of the renal impairment subjects) will be enrolled in the study. Subjects with renal impairment will be enrolled and stratified into three cohorts using their Screening 24 hour urine collection to measured creatinine clearance (CLcr) values (an estimate of Glomerular Filtration Rate): Mild Impairment (CLcr = 51-80 ml/min), Moderate Impairment (CLcr = 31-50 ml/min), and Severe Impairment (CLcr \<31 ml/min, not requiring dialysis). Control subjects will have normal renal function (CLcr \>90 ml/min), as determined by a Screening 24 hour urine collection. The screening visits will occur within 14 days prior to plerixafor administration on study day one. Subjects will be monitored for 10 hours following administration of the study drug. In addition, subjects will return to the clinic at 24 and 48 hours after plerixafor administration for blood samples and safety assessments. This study was previously posted by AnorMED, Inc. In November 2006, AnorMED, Inc. was acquired by Genzyme Corporation. Genzyme Corporation is the sponsor of the trial.
Interventions
DRUGplerixafor
Single dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
Inclusion criteria
* Signed patient informed consent form prior to any study procedures at Screening. * Subject has not consumed alcohol in the 48 hours prior to the administration of study drug. * Subject agrees to refrain from consumption of alcohol for the duration of the trial. * Subject agrees to practice an approved method of contraception for the duration of the study. * White blood cell count ≧3.5\*10\^9/L. * Absolute polymorphonuclear leukocyte count \>2.5\*10\^9/L. * Platelet count \>125\*10\^9/L. * Serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and total bilirubin \<2 times upper limit of normal (ULN). * Negative for Human Immunodeficiency Virus (HIV). * Age: Renal impairment subjects, 18-78 years. Control subjects, 35-78 years. * Creatinine clearance measured from 24-hour urine collection (CLcr u): Renal impairment cohorts, Mild Impairment (CLcr u = 51-80 ml/min), Moderate Impairment (CLcr u = 31-50 ml/min), and Severe Impairment (CLcr u \<31 ml/min, not requiring dialysis). Control subjects, CLcr u \>90 ml/min.
Exclusion criteria
* Known sensitivity to plerixafor or any of its components. * Pregnant or breast-feeding. * Actual body weight exceeds 175% of ideal body mass index. * Subjects judged by the investigator to be at significant risk of failing to comply with the requirements of the protocol. * Any subject who has started new medication within 14 days prior to study drug administration. * Treatment with an investigational product within 30 days prior to trial entry. * Any significant untreated or newly diagnosed medical condition other than renal impairment that in the opinion of the investigator may interfere with the conduct of the study. * Abnormal electrocardiogram with clinically significant rhythm disturbance,(ventricular arrhythmias), or other conduction abnormality that in the opinion of the investigator warrants exclusion of the subject from the trial. * History of clinically significant thrombocytopenia. * Received blood transfusions within 30 days prior to trial entry. * Any subject who requires therapeutic intervention within the 30 days prior to administration of study medication in order to meet the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Normalized Maximum Concentration of Plerixafor (Cmax) | Pre-dose of plerixafor to 24 hours post-plerixafor | Evaluation of Cmax following a single dose of 240 µg/kg plerixafor administered on Day 1. Cmax was normalized by dose. |
| Dose-Normalized Area Under the Plerixafor Concentration Time Curve From Time 0 to 24 Hours Post-dose (AUC0-24h) | Pre-dose of plerixafor to 24 hours post-plerixafor | Evaluation of AUC0-24 hour following a single dose of 240 µg/kg plerixafor administered on Day 1. AUC0-24 was normalized by dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Absolute CD34+ Cell Counts at Day 2 | Baseline, Day 2 | Change in circulating CD34+ cells from baseline to Day 2 (24 hours post-plerixafor) following a single dose of plerixafor. Change from baseline = CD34+ cell count at 24 hours post dose - CD34+ cell count at Baseline. |
| Change From Baseline in Absolute White Blood Cell (WBC) Counts at Day 2 | Baseline and Day 2 | Change in absolute white blood cells from baseline to Day 2 (24 hours post-plerixafor) following a single dose of plerixafor. Change from baseline = absolute white blood cells at 24 hours post dose - absolute white blood cells at Baseline. |
| Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | up to Day 3 | Number of participants with adverse events (AEs) collected from Day 1 (post plerixafor administration) to Day 3. AEs were graded by the investigator using the World Health Organization (WHO) Adverse Event Grading Scale and were assessed for severity (mild, moderate, severe, life-threatening) and relatedness to study treatment (5 point scale from 'not related' to 'definitely related'). |
Countries
United States
Participant flow
Pre-assignment details
Cohort enrollment into the study was staged based on baseline creatinine clearance levels, with moderate renal impairment and control participants enrolled first. Severe renal impairment were enrolled following completion of the moderate renal impairment. Participants with mild renal impairment were enrolled last.
Participants by arm
| Arm | Count |
|---|---|
| Normal Renal Function Participants with normal renal function (creatinine clearance (CLcr) \> 90 ml/min) used as a control. Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | 6 |
| Mild Renal Impairment Participants with mild renal impairment (CLcr = 51 to 80 mL/min). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | 5 |
| Moderate Renal Impairment Participants with moderate renal impairment (CLcr = 31 to 50 mL/min). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | 6 |
| Severe Renal Impairment Participants with severe renal impairment (CLcr \< 31 mL/min, not requiring dialysis). Participants treated with one dose of plerixafor (240 µg/kg) administered by subcutaneous (SC) injection. | 6 |
| Total | 23 |
Baseline characteristics
| Characteristic | Normal Renal Function | Mild Renal Impairment | Moderate Renal Impairment | Severe Renal Impairment | Total |
|---|---|---|---|---|---|
| Age, Continuous | 42.3 years STANDARD_DEVIATION 5.5 | 56.2 years STANDARD_DEVIATION 14.45 | 65.0 years STANDARD_DEVIATION 5.83 | 55.7 years STANDARD_DEVIATION 11.98 | 54.7 years STANDARD_DEVIATION 12.51 |
| Race/Ethnicity, Customized African-American | 4 participants | 1 participants | 2 participants | 1 participants | 8 participants |
| Race/Ethnicity, Customized Caucasian | 1 participants | 3 participants | 3 participants | 5 participants | 12 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 1 participants | 1 participants | 1 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 4 Participants | 2 Participants | 4 Participants | 2 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 6 | 4 / 6 | 2 / 5 | 5 / 6 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 6 |
Outcome results
Primary
Dose-Normalized Area Under the Plerixafor Concentration Time Curve From Time 0 to 24 Hours Post-dose (AUC0-24h)
Evaluation of AUC0-24 hour following a single dose of 240 µg/kg plerixafor administered on Day 1. AUC0-24 was normalized by dose.
Time frame: Pre-dose of plerixafor to 24 hours post-plerixafor
Population: Intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Dose-Normalized Area Under the Plerixafor Concentration Time Curve From Time 0 to 24 Hours Post-dose (AUC0-24h) | 0.2277 hr*ng/mL/ug | Standard Deviation 0.036 |
| Mild Renal Impairment | Dose-Normalized Area Under the Plerixafor Concentration Time Curve From Time 0 to 24 Hours Post-dose (AUC0-24h) | 0.2866 hr*ng/mL/ug | Standard Deviation 0.0854 |
| Moderate Renal Impairment | Dose-Normalized Area Under the Plerixafor Concentration Time Curve From Time 0 to 24 Hours Post-dose (AUC0-24h) | 0.3550 hr*ng/mL/ug | Standard Deviation 0.0965 |
| Severe Renal Impairment | Dose-Normalized Area Under the Plerixafor Concentration Time Curve From Time 0 to 24 Hours Post-dose (AUC0-24h) | 0.3872 hr*ng/mL/ug | Standard Deviation 0.0688 |
90% CI: [91.86, 161.43]
90% CI: [115.78, 198.09]
90% CI: [129.59, 221.72]
Primary
Dose-Normalized Maximum Concentration of Plerixafor (Cmax)
Evaluation of Cmax following a single dose of 240 µg/kg plerixafor administered on Day 1. Cmax was normalized by dose.
Time frame: Pre-dose of plerixafor to 24 hours post-plerixafor
Population: Intent-to-treat population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Dose-Normalized Maximum Concentration of Plerixafor (Cmax) | 0.0452 ng/mL/ug | Standard Deviation 0.0145 |
| Mild Renal Impairment | Dose-Normalized Maximum Concentration of Plerixafor (Cmax) | 0.0388 ng/mL/ug | Standard Deviation 0.0095 |
| Moderate Renal Impairment | Dose-Normalized Maximum Concentration of Plerixafor (Cmax) | 0.0490 ng/mL/ug | Standard Deviation 0.015 |
| Severe Renal Impairment | Dose-Normalized Maximum Concentration of Plerixafor (Cmax) | 0.0475 ng/mL/ug | Standard Deviation 0.011 |
90% CI: [78.99, 143.87]
90% CI: [79.11, 144.08]
90% CI: [63.59, 119.26]
Secondary
Change From Baseline in Absolute CD34+ Cell Counts at Day 2
Change in circulating CD34+ cells from baseline to Day 2 (24 hours post-plerixafor) following a single dose of plerixafor. Change from baseline = CD34+ cell count at 24 hours post dose - CD34+ cell count at Baseline.
Time frame: Baseline, Day 2
Population: An intent-to-treat approach was used to calculate the outcome measure in each arm/group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Change From Baseline in Absolute CD34+ Cell Counts at Day 2 | 10.5 cells/mm^3 | Standard Deviation 6.19 |
| Mild Renal Impairment | Change From Baseline in Absolute CD34+ Cell Counts at Day 2 | 11.8 cells/mm^3 | Standard Deviation 2.49 |
| Moderate Renal Impairment | Change From Baseline in Absolute CD34+ Cell Counts at Day 2 | 14.3 cells/mm^3 | Standard Deviation 14.24 |
| Severe Renal Impairment | Change From Baseline in Absolute CD34+ Cell Counts at Day 2 | 23.0 cells/mm^3 | Standard Deviation 18.2 |
Secondary
Change From Baseline in Absolute White Blood Cell (WBC) Counts at Day 2
Change in absolute white blood cells from baseline to Day 2 (24 hours post-plerixafor) following a single dose of plerixafor. Change from baseline = absolute white blood cells at 24 hours post dose - absolute white blood cells at Baseline.
Time frame: Baseline and Day 2
Population: An intent-to-treat approach was used to calculate the outcome measure in each arm/group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Change From Baseline in Absolute White Blood Cell (WBC) Counts at Day 2 | 7416.7 cells/mm^3 | Standard Deviation 1986.37 |
| Mild Renal Impairment | Change From Baseline in Absolute White Blood Cell (WBC) Counts at Day 2 | 10540.0 cells/mm^3 | Standard Deviation 2785.32 |
| Moderate Renal Impairment | Change From Baseline in Absolute White Blood Cell (WBC) Counts at Day 2 | 12133.3 cells/mm^3 | Standard Deviation 4501.41 |
| Severe Renal Impairment | Change From Baseline in Absolute White Blood Cell (WBC) Counts at Day 2 | 14975.0 cells/mm^3 | Standard Deviation 5030.82 |
Secondary
Number of Participants in Overall Safety Summary of Adverse Events (TEAE)
Number of participants with adverse events (AEs) collected from Day 1 (post plerixafor administration) to Day 3. AEs were graded by the investigator using the World Health Organization (WHO) Adverse Event Grading Scale and were assessed for severity (mild, moderate, severe, life-threatening) and relatedness to study treatment (5 point scale from 'not related' to 'definitely related').
Time frame: up to Day 3
Population: The safety analyses were performed on the Safety Population which consisted of all subjects who received plerixafor.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Possibly related) | 0 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably related) | 1 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely not related) | 0 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Life Threatening) | 0 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Severe) | 0 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Moderate) | 2 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably not related) | 0 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely related) | 4 participants |
| Normal Renal Function | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Mild) | 3 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely related) | 2 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Possibly related) | 0 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably related) | 0 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Moderate) | 1 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Mild) | 1 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Severe) | 0 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely not related) | 0 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably not related) | 0 participants |
| Mild Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Life Threatening) | 0 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely related) | 2 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Mild) | 3 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Moderate) | 1 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Severe) | 0 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Life Threatening) | 0 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably related) | 2 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Possibly related) | 0 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably not related) | 0 participants |
| Moderate Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely not related) | 0 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Possibly related) | 2 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Life Threatening) | 0 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Severe) | 0 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely not related) | 0 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably not related) | 0 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Moderate) | 2 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Probably related) | 0 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Relationship to Drug (Definitely related) | 2 participants |
| Severe Renal Impairment | Number of Participants in Overall Safety Summary of Adverse Events (TEAE) | AE Severity (Mild) | 2 participants |