End-stage Renal Disease, Relapsed Multiple Myeloma
Conditions
Brief summary
The purpose of this study is to see how the body and the cancer react to carfilzomib, including measuring the amount of the study drug in the blood at certain times following dosing. This study is being done in people with normal kidney function and those with end-stage renal disease to see if they respond differently to the study drug.
Detailed description
Specifically, the purpose of this study is to assess the influence of end-stage renal disease (ESRD) on area under the curve (both area under the curve, from time 0 to the last concentration measured \[AUC0-last\] and area under the curve, from time 0 extrapolated to infinity \[AUC0-inf\]) of carfilzomib 56 mg/m² at Cycle 2 Day 1 (C2D1) in patients with relapsed multiple myeloma.
Interventions
DRUGCarfilzomib
Carfilzomib was administered by IV injection.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. Relapsed multiple myeloma 2. Evaluable disease (serum protein electrophoresis \[SPEP\]/urine protein electrophoresis \[UPEP\]/serum free light chain \[SFLC\] criteria) 3. Received at least 1 prior treatment regimen or line of therapy for multiple myeloma 4. End-stage renal disease (ESRD) on hemodialysis or CrCl ≥ 75 mL/min 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2 6. Adequate organ and bone marrow function 7. Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within the protocol-specified period prior to enrollment Key
Exclusion criteria
1. Immunoglobulin M (IgM) multiple myeloma 2. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 3. Waldenström Macroglobulinemia 4. Active congestive heart failure (NYHA Class III-IV) ischemia, conduction abnormalities 5. Known human immunodeficiency virus (HIV), recent hepatitis B virus (HBV), hepatitis C virus (HCV) 6. Myelodysplastic Syndrome 7. Contraindication to test article, constituents, or required concomitant medications 8. Other investigational drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | Carfilzomib plasma concentrations for pharmacokinetic (PK) analyses were measured by liquid chromatography with tandem mass spectrometry. The lower limit of quantitation (LLOQ) for the assay was 0.3 ng/mL. |
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Half-life (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Clearance (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Mean Residence Time (MRT) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Volume of Distribution at Steady State (Vss) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Terminal Half-life (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Clearance (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Mean Residence Time (MRT) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Volume of Distribution at Steady State (Vss) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Terminal Half-life (T½) of Metabolite PR-389/M14 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Terminal Half-life (T½) of Metabolite PR-413/M15 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Terminal Half-life (T½) of Metabolite PR-519/M16 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Number of Participants With Adverse Events (AEs) | From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 12 October 2015; median duration of treatment was 14 weeks in the normal renal function group and 12 weeks in the ESRD group. | Determination of the severity of all adverse events was assessed following the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Fatal. A Serious AE is an AE that meets one or more of the following criteria: * Death, * Life-threatening experience; * Requires in-patient hospitalization or prolongation of an existing hospitalization, * Results in persistent or significant disability/incapacity, * Is a congenital anomaly/birth defect, * Important medical events that may not result in death, be life-threatening, or require hospitalization. Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship. |
| Maximum Observed Plasma Concentration for Metabolite PR-389/M14 | Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
| Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion. | — |
Countries
Australia, Canada, United States
Participant flow
Recruitment details
Participants were enrolled at 13 investigative study centers (6 in the United States, 2 in Canada, and 5 in Australia) from 29 January 2014 to 25 March 2015. This study is ongoing, results are reported as of the data cut-off date of 12 October 2015.
Pre-assignment details
Participants with relapsed multiple myeloma were enrolled into cohorts according to renal function (normal creatinine clearance (CrCl) or end-stage renal disease (ESRD; patients on hemodialysis)). Renal function was based on calculated CrCl using the Cockcroft-Gault formula at baseline.
Participants by arm
| Arm | Count |
|---|---|
| Normal Renal Function Participants with normal renal function received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. | 15 |
| End Stage Renal Disease Participants with ESRD received carfilzomib 20 mg/m² IV on days 1 and 2 of cycle 1, followed by 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15 and 16 of cycle 2 and all subsequent cycles. | 11 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | On-study at the Data Cut-off Date | 3 | 3 |
Baseline characteristics
| Characteristic | Total | Normal Renal Function | End Stage Renal Disease |
|---|---|---|---|
| Age, Continuous | 64.0 years STANDARD_DEVIATION 7.9 | 64.8 years STANDARD_DEVIATION 8.1 | 62.8 years STANDARD_DEVIATION 7.9 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (Fully active) | 8 participants | 5 participants | 3 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Restrictive but ambulatory) | 17 participants | 10 participants | 7 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 (Ambulatory but unable to work) | 1 participants | 0 participants | 1 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants | 14 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Black | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Not Reported | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 21 participants | 12 participants | 9 participants |
| Sex: Female, Male Female | 11 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 15 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 15 | 10 / 11 |
| serious Total, serious adverse events | 10 / 15 | 9 / 11 |
Outcome results
Primary
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 563 ng*h/mL | Geometric Coefficient of Variation 41.8 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 752 ng*h/mL | Geometric Coefficient of Variation 144.7 |
90% CI: [70.93, 251.73]
Primary
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Carfilzomib plasma concentrations for pharmacokinetic (PK) analyses were measured by liquid chromatography with tandem mass spectrometry. The lower limit of quantitation (LLOQ) for the assay was 0.3 ng/mL.
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. The PK evaluable population is defined as participants with sufficient carfilzomib plasma concentration versus time data for the estimation of PK parameters by non-compartmental analysis on cycle 1, day 16 and/or cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 563 ng*h/mL | Geometric Coefficient of Variation 41.9 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 747 ng*h/mL | Geometric Coefficient of Variation 143.9 |
90% CI: [70.6, 249.63]
Secondary
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population. Participants for whom the extrapolated portion of AUC0-∞ was \> 20% were excluded. AUC0-∞ could not be calculated for the ESRD group as the extrapolated portion (AUCextr) was greater than 20% in all participants.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14 | Cycle 1, Day 16 | 355 ng*h/mL | Geometric Coefficient of Variation 25.1 |
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-389/M14 | Cycle 2, Day 1 | 650 ng*h/mL | Geometric Coefficient of Variation 22.5 |
Secondary
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants for whom the extrapolated portion of AUC0-∞ was \> 20% were excluded.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 7) | 36.2 ng*h/mL | Geometric Coefficient of Variation 54.1 |
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 5) | 63.8 ng*h/mL | Geometric Coefficient of Variation 48 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 7) | 66.4 ng*h/mL | Geometric Coefficient of Variation 48.7 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 5) | 131 ng*h/mL | Geometric Coefficient of Variation 35.8 |
Secondary
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 84.4 ng*h/mL | Geometric Coefficient of Variation 52.4 |
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 148 ng*h/mL | Geometric Coefficient of Variation 51.7 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 89.6 ng*h/mL | Geometric Coefficient of Variation 42.8 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 139 ng*h/mL | Geometric Coefficient of Variation 125.1 |
Secondary
Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants for whom the coefficient of correlation (R²) was \< 0.8 were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 347 ng*h/mL | Geometric Coefficient of Variation 26.3 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 479 ng*h/mL | Geometric Coefficient of Variation 46.6 |
Secondary
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. n indicates the number of participants included in the analyses at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 | Cycle 1, Day 16 (n = 13, 9) | 320 ng*h/mL | Geometric Coefficient of Variation 32.8 |
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 | Cycle 2, Day 1 (n = 10, 8) | 584 ng*h/mL | Geometric Coefficient of Variation 17.5 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 | Cycle 1, Day 16 (n = 13, 9) | 1486 ng*h/mL | Geometric Coefficient of Variation 32.3 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-389/M14 | Cycle 2, Day 1 (n = 10, 8) | 2086 ng*h/mL | Geometric Coefficient of Variation 132.8 |
Secondary
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 9) | 33.4 ng*h/mL | Geometric Coefficient of Variation 53.9 |
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 8) | 60.3 ng*h/mL | Geometric Coefficient of Variation 48.4 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 9) | 54.6 ng*h/mL | Geometric Coefficient of Variation 45 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 8) | 86.3 ng*h/mL | Geometric Coefficient of Variation 199.1 |
Secondary
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 82.8 ng*h/mL | Geometric Coefficient of Variation 53.1 |
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 147 ng*h/mL | Geometric Coefficient of Variation 52.8 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 86.8 ng*h/mL | Geometric Coefficient of Variation 44.3 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 138 ng*h/mL | Geometric Coefficient of Variation 126.6 |
Secondary
Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 344 ng*h/mL | Geometric Coefficient of Variation 24.8 |
| End Stage Renal Disease | Area Under the Concentration Time Curve From Time 0 to Last Concentration (AUC0-last) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 480 ng*h/mL | Geometric Coefficient of Variation 36 |
Secondary
Clearance (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Clearance (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 146 liters/hour | Geometric Coefficient of Variation 23 |
| End Stage Renal Disease | Clearance (CL) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 93 liters/hour | Geometric Coefficient of Variation 56.8 |
Secondary
Clearance (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Clearance (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 179 liters/hour | Geometric Coefficient of Variation 38.9 |
| End Stage Renal Disease | Clearance (CL) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 134 liters/hour | Geometric Coefficient of Variation 136.9 |
Secondary
Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 9) | 20.7 ng/mL | Geometric Coefficient of Variation 43.5 |
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 8) | 40.2 ng/mL | Geometric Coefficient of Variation 38.5 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 9) | 25.9 ng/mL | Geometric Coefficient of Variation 42.5 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 8) | 42.3 ng/mL | Geometric Coefficient of Variation 163.9 |
Secondary
Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 93.4 ng/mL | Geometric Coefficient of Variation 40.2 |
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 180 ng/mL | Geometric Coefficient of Variation 40.5 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 90.4 ng/mL | Geometric Coefficient of Variation 48 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 151 ng/mL | Geometric Coefficient of Variation 129.7 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 819 ng/mL | Geometric Coefficient of Variation 29.8 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 1022 ng/mL | Geometric Coefficient of Variation 37.2 |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 1389 ng/mL | Geometric Coefficient of Variation 26.8 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration (Cmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 1567 ng/mL | Geometric Coefficient of Variation 128.8 |
Secondary
Maximum Observed Plasma Concentration for Metabolite PR-389/M14
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Renal Function | Maximum Observed Plasma Concentration for Metabolite PR-389/M14 | Cycle 1, Day 16 (n = 13, 9) | 153 ng/mL | Geometric Coefficient of Variation 25.4 |
| Normal Renal Function | Maximum Observed Plasma Concentration for Metabolite PR-389/M14 | Cycle 2, Day 1 (n = 10, 8) | 302 ng/mL | Geometric Coefficient of Variation 16.5 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration for Metabolite PR-389/M14 | Cycle 1, Day 16 (n = 13, 9) | 413 ng/mL | Geometric Coefficient of Variation 32.9 |
| End Stage Renal Disease | Maximum Observed Plasma Concentration for Metabolite PR-389/M14 | Cycle 2, Day 1 (n = 10, 8) | 595 ng/mL | Geometric Coefficient of Variation 128.4 |
Secondary
Mean Residence Time (MRT) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants with a coefficient of correlation (R²) \< 0.8 were excluded.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Residence Time (MRT) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 0.222 hours | Geometric Coefficient of Variation 16.6 |
| End Stage Renal Disease | Mean Residence Time (MRT) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 0.426 hours | Geometric Coefficient of Variation 152.2 |
Secondary
Mean Residence Time (MRT) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Mean Residence Time (MRT) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 0.135 hours | Geometric Coefficient of Variation 62.6 |
| End Stage Renal Disease | Mean Residence Time (MRT) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 0.245 hours | Geometric Coefficient of Variation 79.9 |
Secondary
Number of Participants With Adverse Events (AEs)
Determination of the severity of all adverse events was assessed following the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, where Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Fatal. A Serious AE is an AE that meets one or more of the following criteria: * Death, * Life-threatening experience; * Requires in-patient hospitalization or prolongation of an existing hospitalization, * Results in persistent or significant disability/incapacity, * Is a congenital anomaly/birth defect, * Important medical events that may not result in death, be life-threatening, or require hospitalization. Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship.
Time frame: From the first dose of study drug up to 30 days after the last dose of study drug as of the data cut-off date of 12 October 2015; median duration of treatment was 14 weeks in the normal renal function group and 12 weeks in the ESRD group.
Population: All treated participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Any adverse event | 15 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Adverse event ≥ Grade 3 | 12 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Serious adverse event | 10 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | AE leading to discontinuation of carfilzomib | 6 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 2 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events | 12 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event ≥ Grade 3 | 7 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse event | 5 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 4 participants |
| Normal Renal Function | Number of Participants With Adverse Events (AEs) | Treatment-related fatal adverse events | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Serious treatment-related adverse event | 2 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Any adverse event | 11 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events | 8 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Adverse event ≥ Grade 3 | 9 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Treatment-related fatal adverse events | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Serious adverse event | 9 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Treatment-related adverse event ≥ Grade 3 | 6 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | AE leading to discontinuation of carfilzomib | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 0 participants |
| End Stage Renal Disease | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 1 participants |
Secondary
Terminal Half-life (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants with a coefficient of correlation (R²) \< 0.8 were excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Terminal Half-life (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 0.387 hours |
| End Stage Renal Disease | Terminal Half-life (T½) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 0.992 hours |
Secondary
Terminal Half-life (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Terminal Half-life (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 0.341 hours |
| End Stage Renal Disease | Terminal Half-life (T½) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 1.25 hours |
Secondary
Terminal Half-life (T½) of Metabolite PR-389/M14
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population. Participants for whom the extrapolated portion of AUC0-∞ was \> 20% were excluded. T½ could not be calculated for the ESRD group as the extrapolated portion (AUCextr) was greater than 20% in all participants.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Renal Function | Terminal Half-life (T½) of Metabolite PR-389/M14 | Cycle 1, Day 16 | 1.46 hours |
| Normal Renal Function | Terminal Half-life (T½) of Metabolite PR-389/M14 | Cycle 2, Day 1 | 1.10 hours |
Secondary
Terminal Half-life (T½) of Metabolite PR-413/M15
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site. Participants for whom the extrapolated portion of AUC0-∞ was \> 20% were excluded.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Renal Function | Terminal Half-life (T½) of Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 7) | 1.07 hours |
| Normal Renal Function | Terminal Half-life (T½) of Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 5) | 0.962 hours |
| End Stage Renal Disease | Terminal Half-life (T½) of Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 7) | 1.41 hours |
| End Stage Renal Disease | Terminal Half-life (T½) of Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 5) | 1.37 hours |
Secondary
Terminal Half-life (T½) of Metabolite PR-519/M16
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Renal Function | Terminal Half-life (T½) of Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 0.705 hours |
| Normal Renal Function | Terminal Half-life (T½) of Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 0.617 hours |
| End Stage Renal Disease | Terminal Half-life (T½) of Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 0.687 hours |
| End Stage Renal Disease | Terminal Half-life (T½) of Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 0.721 hours |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 1, Day 16 (n = 13, 9) | 1.00 hours |
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 2, Day 1 (n = 10, 8) | 0.983 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 1, Day 16 (n = 13, 9) | 1.50 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 2, Day 1 (n = 10, 8) | 2.00 hours |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 9) | 0.833 hours |
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 8) | 0.667 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 1, Day 16 (n = 13, 9) | 0.767 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 2, Day 1 (n = 10, 8) | 0.750 hours |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16
Time frame: Cycle 1, day 16 and cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population; one participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 0.617 hours |
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 0.525 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 1, Day 16 (n = 13, 9) | 0.600 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 2, Day 1 (n = 10, 8) | 0.533 hours |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 0.583 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 0.467 hours |
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Renal Function | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 0.467 hours |
| End Stage Renal Disease | Time to Maximum Observed Plasma Concentration (Tmax) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 0.467 hours |
Secondary
Volume of Distribution at Steady State (Vss) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1
Time frame: Cycle 1, day 16 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 1, day 16. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Volume of Distribution at Steady State (Vss) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 32.0 liters | Geometric Coefficient of Variation 29.7 |
| End Stage Renal Disease | Volume of Distribution at Steady State (Vss) of Carfilzomib Following 27 mg/m² Carfilzomib on Day 16 of Cycle 1 | 53.0 liters | Geometric Coefficient of Variation 185.5 |
Secondary
Volume of Distribution at Steady State (Vss) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2
Time frame: Cycle 2, day 1 at predose, 15 minutes post start of infusion, immediately before the end of infusion, and at 5, 15, and 30 minutes, and 1, 2, and 4 hours after the end of the infusion.
Population: PK evaluable population for cycle 2, day 1. One participant was excluded due to samples taken from the infusion arm, distal to the infusion site.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Renal Function | Volume of Distribution at Steady State (Vss) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 24.1 liters | Geometric Coefficient of Variation 44.8 |
| End Stage Renal Disease | Volume of Distribution at Steady State (Vss) of Carfilzomib Following 56 mg/m² Carfilzomib on Day 1 of Cycle 2 | 32.8 liters | Geometric Coefficient of Variation 133.9 |