Hematologic Malignancies, Hepatic Impairment, Solid Tumors
Conditions
Brief summary
The purpose of this study is to compare the safety and efficacy of 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 varying degrees of liver function to see if they respond differently to the study drug.
Interventions
DRUGCarfilzomib
Carfilzomib was administered by IV injection over 30 minutes
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 or progressive advanced malignancies (solid tumors or hematologic malignancies) 2. At least ≥ 2 prior treatment regimens for the underlying malignancy 3. Confirmed advanced solid tumor or hematologic malignancy 4. Measurable or evaluable disease 5. Clinical diagnosis of chronic hepatic impairment that is stable with no acute worsening of liver failure within one month prior to enrollment. Hepatic impairment will be assessed as per National Cancer Institute Organ Dysfunction Working Group Criteria (NCI-ODWG) schema and will fall into one of the following three categories: * Cohort 2 (mild): Bilirubin \> 1-1.5 × upper limit of the normal range (ULN) or aspartate aminotransferase (AST) \> ULN, but bilirubin ≤ ULN * Cohort 3 (moderate): ≥ 1.6-3 × ULN; any AST * Cohort 4 (severe): Bilirubin \> 3 × ULN; any AST Exception to Inclusion Criterion #5 for Subjects with Normal Hepatic Function: All subjects enrolled with normal hepatic function (N=10) must meet all inclusion criteria as outlined with the exception of Inclusion Criterion #5, which should be substituted with the following criterion to be enrolled into the study: \- Cohort 1 (normal hepatic function): Bilirubin ≤ ULN; AST ≤ ULN 6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2 7. Left ventricular ejection fraction (LVEF) ≥ 40% 8. Adequate renal function (calculated creatinine clearance ≥ 30 mL/min) 9. 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. Subjects with symptomatic brain metastasis or central nervous system (CNS) disease 2. Significant neurotoxicity (Grade 2 with pain or higher) at the time of enrolment 3. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) infection (Exception: Subjects with chronic or cleared HBV and HCV infection and stable liver function tests \[bilirubin, AST\] will be allowed)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | The area under the curve from time zero (defined as the start of carfilzomib infusion) to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. |
| Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m² | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m² | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Tmax) of Carfilzomib 27 mg/m² | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 of Carfilzomib 27 mg/m² | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 of Carfilzomib 27 mg/m² | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 27 mg/m² | Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 27 mg/m² | Cycle 1 day 16 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | The area under the curve from time zero to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. |
| Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) before the end of infusion, and at 5, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. | The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib. |
| Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 of Carfilzomib 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 of Carfilzomib 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 56 mg/m² | Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Cmax) for Metabolite PR-389/M14 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 for Metabolite PR-389/M14 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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) for Metabolite PR-389/M14 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 for Metabolite PR-413/M15 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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) for Metabolite PR-413/M15 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 for Metabolite PR-519/M16 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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) for Metabolite PR-519/M16 | Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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 carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks | Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship. Adverse events were graded using National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, on a scale from 1 (mild) to 5 (death). |
Countries
France, Netherlands, United Kingdom, United States
Participant flow
Pre-assignment details
Participants were assigned to 1 of 4 cohorts with varying degrees of hepatic impairment defined by the National Cancer Institute Organ Dysfunction Working Group Criteria (NCI-ODWG) schema for hepatic function. Completed indicates participants who completed the safety follow-up visit 30 days after the last dose of carfilzomib.
Participants by arm
| Arm | Count |
|---|---|
| Normal Hepatic Function Participants with normal hepatic function (bilirubin and aspartate aminotransferase (AST) ≤ the upper limit of normal (ULN)) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | 11 |
| Mild Hepatic Impairment Participants with mild hepatic impairment (bilirubin \> 1-1.5 x ULN or AST \> ULN, but bilirubin ≤ ULN) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | 17 |
| Moderate Hepatic Impairment Participants with moderate hepatic impairment (bilirubin \> 1.5-3 x ULN, any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | 14 |
| Severe Hepatic Impairment Participants with severe hepatic impairment (bilirubin \> 3 x ULN; any AST) received carfilzomib 20 mg/m² administered by intravenous (IV) infusion on days 1 and 2 of cycle 1, followed by a planned step-up to 27 mg/m² IV on days 8, 9, 15, and 16 of cycle 1. Participants who adequately tolerated dosing at 27 mg/m² in cycle 1 received carfilzomib 56 mg/m² IV on days 1, 2, 8, 9, 15, and 16 of cycle 2 and subsequent 28-day cycles until confirmed progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death. | 4 |
| Total | 46 |
Baseline characteristics
| Characteristic | Mild Hepatic Impairment | Moderate Hepatic Impairment | Severe Hepatic Impairment | Normal Hepatic Function | Total |
|---|---|---|---|---|---|
| Age, Continuous | 59.5 years STANDARD_DEVIATION 9.1 | 61.0 years STANDARD_DEVIATION 7.9 | 56.3 years STANDARD_DEVIATION 10.9 | 68.5 years STANDARD_DEVIATION 8.2 | 61.8 years STANDARD_DEVIATION 9.3 |
| Age, Customized < 65 years | 12 participants | 8 participants | 3 participants | 3 participants | 26 participants |
| Age, Customized ≥ 65 years | 5 participants | 6 participants | 1 participants | 8 participants | 20 participants |
| Race/Ethnicity, Customized Black | 1 participants | 1 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Not reported | 3 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Race/Ethnicity, Customized White | 13 participants | 13 participants | 4 participants | 11 participants | 41 participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 3 Participants | 2 Participants | 18 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 1 Participants | 9 Participants | 28 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 | 10 / 11 | 17 / 17 | 14 / 14 | 3 / 4 |
| serious Total, serious adverse events | 3 / 11 | 10 / 17 | 8 / 14 | 4 / 4 |
Outcome results
Primary
Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m²
The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m² | 348 ng*hr/mL | Geometric Coefficient of Variation 35.4 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m² | 529 ng*hr/mL | Geometric Coefficient of Variation 40.3 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 27 mg/m² | 500 ng*hr/mL | Geometric Coefficient of Variation 38.4 |
Comparison: To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-inf an ANOVA of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.p-value: 0.0213795% CI: [113.59, 202.96]ANOVA
Comparison: To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-inf an ANOVA of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.p-value: 0.0724795% CI: [103.28, 199.45]ANOVA
Primary
Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m²
The area under the curve from time zero (defined as the start of carfilzomib infusion) to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 27 mg/m² on day 16 of cycle 1 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population, defined as participants who received the intended carfilzomib dose (27 or 56 mg/m²) and who had plasma concentration versus time data for the estimation of each pharmacokinetic (PK) parameter by a non-compartmental analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² | 378 ng*hr/mL | Geometric Coefficient of Variation 40.8 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² | 546 ng*hr/mL | Geometric Coefficient of Variation 39.2 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 27 mg/m² | 477 ng*hr/mL | Geometric Coefficient of Variation 33.1 |
Comparison: To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-last an analysis of variance (ANOVA) of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.p-value: 0.0223295% CI: [111.48, 187.12]ANOVA
Comparison: To assess the effect of hepatic impairment relative to participants with normal hepatic function on AUC0-last an ANOVA of the log-transformed plasma PK parameters was performed. The ANOVA model included hepatic impairment as a fixed effect.p-value: 0.181295% CI: [94.59, 168.06]ANOVA
Secondary
Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 400 ng*hr/mL | Geometric Coefficient of Variation 19.3 |
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 834 ng*hr/mL | Geometric Coefficient of Variation 6.3 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 432 ng*hr/mL | Geometric Coefficient of Variation 29.9 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 770 ng*hr/mL | Geometric Coefficient of Variation 27.2 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 437 ng*hr/mL | Geometric Coefficient of Variation 32.7 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 843 ng*hr/mL | Geometric Coefficient of Variation 22.3 |
Secondary
Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 56.6 ng*hr/mL | Geometric Coefficient of Variation 43.7 |
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 116 ng*hr/mL | Geometric Coefficient of Variation 36.9 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 60.8 ng*hr/mL | Geometric Coefficient of Variation 32.6 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 132 ng*hr/mL | Geometric Coefficient of Variation 41 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 92.9 ng*hr/mL | Geometric Coefficient of Variation 41.7 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 186 ng*hr/mL | Geometric Coefficient of Variation 18.2 |
Secondary
Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 127 ng*hr/mL | Geometric Coefficient of Variation 27.8 |
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0 | 281 ng*hr/mL | Geometric Coefficient of Variation 25.6 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 138 ng*hr/mL | Geometric Coefficient of Variation 44.9 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0 | 314 ng*hr/mL | Geometric Coefficient of Variation 42.7 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 235 ng*hr/mL | Geometric Coefficient of Variation 39.4 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0 | 465 ng*hr/mL | Geometric Coefficient of Variation 24.4 |
Secondary
Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m²
The area under the curve from time zero extrapolated to infinity (AUC0-inf) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² | 609 ng*hr/mL | Geometric Coefficient of Variation 99.6 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² | 1108 ng*hr/mL | Geometric Coefficient of Variation 73.7 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Carfilzomib 56 mg/m² | 929 ng*hr/mL | Geometric Coefficient of Variation 46.2 |
Secondary
Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population, defined as all participants who had adequate carfilzomib exposure and plasma concentration versus time data for the estimation of PK parameters by a non-compartmental analysis at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 837 ng*hr/mL | Geometric Coefficient of Variation 26.8 |
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 463 ng*hr/mL | Geometric Coefficient of Variation 42.5 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 417 ng*hr/mL | Geometric Coefficient of Variation 30.5 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 752 ng*hr/mL | Geometric Coefficient of Variation 29.7 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 385 ng*hr/mL | Geometric Coefficient of Variation 26.8 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 786 ng*hr/mL | Geometric Coefficient of Variation 20.3 |
Secondary
Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 50.1 ng*hr/mL | Geometric Coefficient of Variation 39.5 |
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 106 ng*hr/mL | Geometric Coefficient of Variation 33.7 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 56.7 ng*hr/mL | Geometric Coefficient of Variation 33.9 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 119 ng*hr/mL | Geometric Coefficient of Variation 38.9 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 85.5 ng*hr/mL | Geometric Coefficient of Variation 36.6 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 173 ng*hr/mL | Geometric Coefficient of Variation 17.8 |
Secondary
Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 125 ng*hr/mL | Geometric Coefficient of Variation 27.6 |
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 278 ng*hr/mL | Geometric Coefficient of Variation 23.4 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 136 ng*hr/mL | Geometric Coefficient of Variation 45.2 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 311 ng*hr/mL | Geometric Coefficient of Variation 42.9 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 228 ng*hr/mL | Geometric Coefficient of Variation 37.3 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 463 ng*hr/mL | Geometric Coefficient of Variation 24.5 |
Secondary
Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m²
The area under the curve from time zero to the last concentration measured (AUC0-last) following intravenous administration of carfilzomib 56 mg/m² on day 1 of cycle 2 was calculated using a non-compartmental approach, from the individual plasma concentration profiles of carfilzomib.
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² | 765 ng*hr/mL | Geometric Coefficient of Variation 100.5 |
| Mild Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² | 1107 ng*hr/mL | Geometric Coefficient of Variation 73.7 |
| Moderate Hepatic Impairment | Area Under the Concentration Time Curve From Time Zero to Last Concentration Measured (AUC0-last) of Carfilzomib 56 mg/m² | 927 ng*hr/mL | Geometric Coefficient of Variation 45.8 |
Secondary
Clearance of Carfilzomib 27 mg/m²
Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Clearance of Carfilzomib 27 mg/m² | 157 L/hour | Geometric Coefficient of Variation 32.5 |
| Mild Hepatic Impairment | Clearance of Carfilzomib 27 mg/m² | 86.4 L/hour | Geometric Coefficient of Variation 50.9 |
| Moderate Hepatic Impairment | Clearance of Carfilzomib 27 mg/m² | 103 L/hour | Geometric Coefficient of Variation 43.9 |
Secondary
Clearance of Carfilzomib 56 mg/m²
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Clearance of Carfilzomib 56 mg/m² | 181 L/hour | Geometric Coefficient of Variation 95.9 |
| Mild Hepatic Impairment | Clearance of Carfilzomib 56 mg/m² | 92.0 L/hour | Geometric Coefficient of Variation 77.2 |
| Moderate Hepatic Impairment | Clearance of Carfilzomib 56 mg/m² | 121 L/hour | Geometric Coefficient of Variation 43.5 |
Secondary
Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 189 ng/mL | Geometric Coefficient of Variation 32.5 |
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 381 ng/mL | Geometric Coefficient of Variation 15 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 198 ng/mL | Geometric Coefficient of Variation 22.7 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 345 ng/mL | Geometric Coefficient of Variation 25.9 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 201 ng/mL | Geometric Coefficient of Variation 26.5 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 513 ng/mL | Geometric Coefficient of Variation 24.3 |
Secondary
Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 27.8 ng/mL | Geometric Coefficient of Variation 30.5 |
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 59.4 ng/mL | Geometric Coefficient of Variation 27.5 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 33.9 ng/mL | Geometric Coefficient of Variation 30.7 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 66.0 ng/mL | Geometric Coefficient of Variation 37.2 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 46.3 ng/mL | Geometric Coefficient of Variation 26.6 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 103 ng/mL | Geometric Coefficient of Variation 19.5 |
Secondary
Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 145 ng/mL | Geometric Coefficient of Variation 30.7 |
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 314 ng/mL | Geometric Coefficient of Variation 33.6 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 160 ng/mL | Geometric Coefficient of Variation 42 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 349 ng/mL | Geometric Coefficient of Variation 39.5 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 257 ng/mL | Geometric Coefficient of Variation 43.6 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 546 ng/mL | Geometric Coefficient of Variation 23.4 |
Secondary
Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m²
Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m² | 932 ng/mL | Geometric Coefficient of Variation 58.4 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m² | 1290 ng/mL | Geometric Coefficient of Variation 47.5 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Carfilzomib 27 mg/m² | 1020 ng/mL | Geometric Coefficient of Variation 43.7 |
Secondary
Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m²
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² | 1697 ng/mL | Geometric Coefficient of Variation 93.7 |
| Mild Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² | 2733 ng/mL | Geometric Coefficient of Variation 67 |
| Moderate Hepatic Impairment | Maximum Plasma Concentration (Cmax) of Carfilzomib 56 mg/m² | 2119 ng/mL | Geometric Coefficient of Variation 47.9 |
Secondary
Mean Residence Time (MRT) for Metabolite PR-389/M14
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Mean Residence Time (MRT) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 2.25 hours | Geometric Coefficient of Variation 10.8 |
| Normal Hepatic Function | Mean Residence Time (MRT) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 2.42 hours | Geometric Coefficient of Variation 11.4 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 2.27 hours | Geometric Coefficient of Variation 15.8 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 2.13 hours | Geometric Coefficient of Variation 12.2 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 1.78 hours | Geometric Coefficient of Variation 11.2 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 2.14 hours | Geometric Coefficient of Variation 16 |
Secondary
Mean Residence Time (MRT) for Metabolite PR-413/M15
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Mean Residence Time (MRT) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 2.13 hours | Geometric Coefficient of Variation 15.8 |
| Normal Hepatic Function | Mean Residence Time (MRT) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 1.96 hours | Geometric Coefficient of Variation 18.9 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 2.02 hours | Geometric Coefficient of Variation 8.8 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 2.09 hours | Geometric Coefficient of Variation 8 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 2.04 hours | Geometric Coefficient of Variation 14.6 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 1.83 hours | Geometric Coefficient of Variation 8.9 |
Secondary
Mean Residence Time (MRT) for Metabolite PR-519/M16
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Mean Residence Time (MRT) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 1.01 hours | Geometric Coefficient of Variation 11.3 |
| Normal Hepatic Function | Mean Residence Time (MRT) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.994 hours | Geometric Coefficient of Variation 9 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 0.961 hours | Geometric Coefficient of Variation 29.1 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 1.00 hours | Geometric Coefficient of Variation 14.2 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 0.994 hours | Geometric Coefficient of Variation 13.3 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.909 hours | Geometric Coefficient of Variation 7.8 |
Secondary
Mean Residence Time (MRT) of Carfilzomib 27 mg/m²
Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Mean Residence Time (MRT) of Carfilzomib 27 mg/m² | 0.108 hours | Geometric Coefficient of Variation 60.6 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) of Carfilzomib 27 mg/m² | 0.167 hours | Geometric Coefficient of Variation 45.7 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) of Carfilzomib 27 mg/m² | 0.235 hours | Geometric Coefficient of Variation 70.4 |
Secondary
Mean Residence Time (MRT) of Carfilzomib 56 mg/m²
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Mean Residence Time (MRT) of Carfilzomib 56 mg/m² | 0.0834 hours | Geometric Coefficient of Variation 195.6 |
| Mild Hepatic Impairment | Mean Residence Time (MRT) of Carfilzomib 56 mg/m² | 0.161 hours | Geometric Coefficient of Variation 43.6 |
| Moderate Hepatic Impairment | Mean Residence Time (MRT) of Carfilzomib 56 mg/m² | 0.164 hours | Geometric Coefficient of Variation 30.7 |
Secondary
Number of Participants With Adverse Events (AEs)
Treatment-related adverse events (TRAEs) are adverse events considered related to carfilzomib by the investigator, including those with unknown relationship. Adverse events were graded using National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03, on a scale from 1 (mild) to 5 (death).
Time frame: From the first dose of carfilzomib until 30 days after last dose; the overall median duration of treatment was 4.2 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Treatment-related fatal adverse events | 0 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAE) | 8 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 1 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of carfilzomib | 1 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 1 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Adverse event Grade ≥ 3 | 7 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Any adverse event | 10 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse events | 0 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events Grade ≥ 3 | 2 participants |
| Normal Hepatic Function | Number of Participants With Adverse Events (AEs) | Serious adverse events | 3 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 4 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Any adverse event | 17 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Adverse event Grade ≥ 3 | 12 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Serious adverse events | 10 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of carfilzomib | 2 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAE) | 13 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events Grade ≥ 3 | 5 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse events | 3 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 0 participants |
| Mild Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related fatal adverse events | 2 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Serious adverse events | 8 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAE) | 12 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Any adverse event | 14 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events Grade ≥ 3 | 8 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Adverse event Grade ≥ 3 | 13 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse events | 4 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related fatal adverse events | 0 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 3 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of carfilzomib | 4 participants |
| Moderate Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 1 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Fatal adverse events | 3 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | TRAE leading to discontinuation of carfilzomib | 0 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related serious adverse events | 0 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events (TRAE) | 1 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Adverse event Grade ≥ 3 | 3 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Any adverse event | 4 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Leading to discontinuation of carfilzomib | 0 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related adverse events Grade ≥ 3 | 0 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Serious adverse events | 4 participants |
| Severe Hepatic Impairment | Number of Participants With Adverse Events (AEs) | Treatment-related fatal adverse events | 0 participants |
Secondary
Terminal Half-life for Metabolite PR-389/M14
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Terminal Half-life for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 1.42 hours | Geometric Coefficient of Variation 10.3 |
| Normal Hepatic Function | Terminal Half-life for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 1.32 hours | Geometric Coefficient of Variation 15.3 |
| Mild Hepatic Impairment | Terminal Half-life for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 1.20 hours | Geometric Coefficient of Variation 13.7 |
| Mild Hepatic Impairment | Terminal Half-life for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 1.30 hours | Geometric Coefficient of Variation 16.1 |
| Moderate Hepatic Impairment | Terminal Half-life for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 4, 11, 8, 0 | 1.26 hours | Geometric Coefficient of Variation 18 |
| Moderate Hepatic Impairment | Terminal Half-life for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 4, 6, 5, 0 | 1.07 hours | Geometric Coefficient of Variation 13.6 |
Secondary
Terminal Half-life for Metabolite PR-413/M15
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Terminal Half-life for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 1.34 hours | Geometric Coefficient of Variation 18.9 |
| Normal Hepatic Function | Terminal Half-life for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 1.18 hours | Geometric Coefficient of Variation 21.8 |
| Mild Hepatic Impairment | Terminal Half-life for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 1.25 hours | Geometric Coefficient of Variation 13.6 |
| Mild Hepatic Impairment | Terminal Half-life for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 1.24 hours | Geometric Coefficient of Variation 10.2 |
| Moderate Hepatic Impairment | Terminal Half-life for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 13, 8, 0 | 1.23 hours | Geometric Coefficient of Variation 17.6 |
| Moderate Hepatic Impairment | Terminal Half-life for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 1.07 hours | Geometric Coefficient of Variation 16 |
Secondary
Terminal Half-life for Metabolite PR-519/M16
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Normal Hepatic Function | Terminal Half-life for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 0.786 hours | Geometric Coefficient of Variation 14 |
| Normal Hepatic Function | Terminal Half-life for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0 | 0.748 hours | Geometric Coefficient of Variation 22.2 |
| Mild Hepatic Impairment | Terminal Half-life for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 0.728 hours | Geometric Coefficient of Variation 22.6 |
| Mild Hepatic Impairment | Terminal Half-life for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0 | 0.680 hours | Geometric Coefficient of Variation 10.7 |
| Moderate Hepatic Impairment | Terminal Half-life for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 8, 0 | 0.673 hours | Geometric Coefficient of Variation 13.6 |
| Moderate Hepatic Impairment | Terminal Half-life for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 7, 8, 5, 0 | 0.601 hours | Geometric Coefficient of Variation 8.2 |
Secondary
Terminal Half-life of Carfilzomib 27 mg/m²
Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Terminal Half-life of Carfilzomib 27 mg/m² | 0.469 hours | Geometric Coefficient of Variation 22.8 |
| Mild Hepatic Impairment | Terminal Half-life of Carfilzomib 27 mg/m² | 0.541 hours | Geometric Coefficient of Variation 75.9 |
| Moderate Hepatic Impairment | Terminal Half-life of Carfilzomib 27 mg/m² | 0.511 hours | Geometric Coefficient of Variation 219.4 |
Secondary
Terminal Half-life of Carfilzomib 56 mg/m²
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Terminal Half-life of Carfilzomib 56 mg/m² | 0.508 hours | Geometric Coefficient of Variation 54.7 |
| Mild Hepatic Impairment | Terminal Half-life of Carfilzomib 56 mg/m² | 0.621 hours | Geometric Coefficient of Variation 47.7 |
| Moderate Hepatic Impairment | Terminal Half-life of Carfilzomib 56 mg/m² | 0.740 hours | Geometric Coefficient of Variation 137.7 |
Secondary
Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.867 hours |
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.842 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.792 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.992 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.750 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-389/M14 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.750 hours |
Secondary
Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.750 hours |
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.717 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.767 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.800 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.650 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-413/M15 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.750 hours |
Secondary
Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16
Time frame: Cycle 1 day 16 and cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.500 hours |
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.483 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.600 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.592 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 1 Day 16 (27 mg/m²); N = 10, 14, 9, 0 | 0.700 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) for Metabolite PR-519/M16 | Cycle 2 Day 1 (56 mg/m²); N = 8, 8, 5, 0 | 0.583 hours |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m²
Time frame: Cycle 1 day 16, pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m² | 0.292 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m² | 0.458 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 27 mg/m² | 0.483 hours |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m²
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Hepatic Function | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² | 0.300 hours |
| Mild Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² | 0.408 hours |
| Moderate Hepatic Impairment | Time to Maximum Plasma Concentration (Tmax) of Carfilzomib 56 mg/m² | 0.400 hours |
Secondary
Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m²
Time frame: Cycle 1 day 16 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m² | 16.9 liters | Geometric Coefficient of Variation 37 |
| Mild Hepatic Impairment | Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m² | 14.4 liters | Geometric Coefficient of Variation 58.1 |
| Moderate Hepatic Impairment | Volume of Distribution at Steady State (Vss) of Carfilzomib 27 mg/m² | 24.2 liters | Geometric Coefficient of Variation 66 |
Secondary
Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m²
Time frame: Cycle 2 day 1 pre-dose, 15 minutes after the start of infusion, immediately (within 2 minutes) 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: Pharmacokinetic-evaluable population with data to allow terminal phase characterization
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Normal Hepatic Function | Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m² | 15.0 liters | Geometric Coefficient of Variation 52.2 |
| Mild Hepatic Impairment | Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m² | 14.8 liters | Geometric Coefficient of Variation 51.9 |
| Moderate Hepatic Impairment | Volume of Distribution at Steady State (Vss) of Carfilzomib 56 mg/m² | 19.8 liters | Geometric Coefficient of Variation 36.7 |