Hepatic Insufficiency, Renal Insufficiency
Conditions
Keywords
Renal Impairment, Pharmacokinetics, Hepatic impairment, Envisaged indication: Treatment of cancer
Brief summary
To evaluate the pharmacokinetics and safety of copanlisib in subjects with impaired hepatic or renal function in comparison to healthy subjects
Interventions
12mg single dose, intravenous on Day 0
Sponsors
Bayer
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
All subjects - Male and female subjects between 18 and 80 years of age with a body mass index above 18.0 and below 34.0 kg / m² and a body weight of above or equal 50 kg. Healthy subjects \- Healthy subjects as determined by absence of clinically significant deviation from normal in medical history, physical examination, vital signs, electrocardiograms, and clinical laboratory determinations. eGFR ≥ 90 mL/min/1.73 m² (according to Modification of Diet in Renal Disease \[MDRD\] formula). Subjects with moderate or severe hepatic impairment * Subjects with confirmed liver cirrhosis by at least one of the following Criteria: histologically by prior liver biopsy showing cirrhosis, liver imaging (computer tomography, and/or ultrasound and/or magnetic resonance imaging scans, and/or fibroscan), or laparoscopy. * Child-Pugh Clinical Assessment Score 7 to 9 (moderate) or Score 10 to 15 (severe). Subjects with severe renal impairment * Subjects with severe renal impairment with an estimated glomerular filtration rate 15-29 mL/min/1.73 m² according to MDRD formula. * Subjects with stable renal disease: no significant change in renal function as evidenced by serum creatinine value within ±25% from the last determination, obtained within at least 3 months before study entry and the absence of the need to start dialysis in the next 3 months.
Exclusion criteria
All subjects * Active coronary artery disease or myocardial infarction within 6 months of study entry. Immuno-compromised subjects including known history/seropositivity of human immunodeficiency virus (HIV). * Other concurrent severe and/or uncontrolled medical conditions (e.g. current diagnosis of type 1 or type 2 diabetes mellitus and with HbA1c \>8.5%) that could cause unacceptable safety risks or compromise compliance with protocol. * Previous or concurrent history of malignancies within 5 years prior to study treatment except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder cancer as well as localized prostate cancer. * Uncontrolled hypertension despite optimal medical management (per investigator's assessment). * Administration of strong CYP3A4 inhibitors or inducers within 2 weeks prior to dosing and during study conduct. (A list of these medications can be found in Section 16.6 of the protocol. However, this list may not be comprehensive). Subjects with moderate or severe hepatic impairment * Symptoms or history of encephalopathy (Grade III or worse) * Failure of any other major organ other than the liver; severe infection, or any clinically significant illness within 4 weeks prior to study drug administration * Renal failure with an eGFR \<35 mL/min/1.73 m² Subjects with severe renal impairment * Acute renal failure at study entry * Nephrotic syndrome * Failure of any other major organ other than the kidney * Acute hepatorenal syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) of Copanlisib in Plasma. | before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion | Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
| Area Under the Concentration vs. Time Curve From Zero to Infinity (AUC) of Copanlisib in Plasma. | before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion | AUC refers to area under the concentration vs time curve from 0 to infinity which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
| Area Under the Concentration-time Curve of Copanlisib in Plasma Over the Time Interval From 0 to 168 h. | before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion | AUC(0-168) refers to AUC from time 0 to 168 hr which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Concentration (Cmax) of Metabolite M-1. | before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion | The morpholinone derivative M-1 is a minor copanlisib metabolite in plasma. The PK of metabolite M-1 is routinely analyzed in addition to the PK of the parent compound, although M-1 is not considered to be a major metabolite. Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Up to 30 days after end of treatment with study drug | Adverse events are considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication. |
| Area Under the Concentration-time Curve of Metabolite M-1 in Plasma Over the Time Interval From 0 to 168 h. | before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion | The morpholinone derivative M-1 is a minor copanlisib metabolite in plasma. The PK of metabolite M-1 is routinely analyzed in addition to the PK of the parent compound, although M-1 is not considered to be a major metabolite. AUC from time 0 to 168h which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Up to 30 days after end of treatment with study drug | Adverse events are considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication. |
Countries
Germany, Romania
Participant flow
Recruitment details
Study was conducted in Germany and Romania between 14 Jun 2017 (first patient's first visit) and 13 Mar 2020 (last patient's last visit).
Pre-assignment details
50 participants were screened in study. 16 were screen failure and 4 withdrew from study. 30 participants were assigned to study arms.
Participants by arm
| Arm | Count |
|---|---|
| Moderate Hepatic Impairment Group Child-Pugh B (score 7-9) at the screening visit | 8 |
| Severe Hepatic Impairment Group Child-Pugh C (score 10-15) at the screening visit | 6 |
| Severe Renal Impairment Group eGFR 15-29 mL/min/1.73 m\^2 at the screening visit based on the Modification of Diet in Renal Disease (MDRD) equation | 8 |
| Healthy Participants Normal hepatic and renal function group | 8 |
| Total | 30 |
Baseline characteristics
| Characteristic | Moderate Hepatic Impairment Group | Total | Healthy Participants | Severe Renal Impairment Group | Severe Hepatic Impairment Group |
|---|---|---|---|---|---|
| Age, Continuous | 65.5 years STANDARD_DEVIATION 9.4 | 60.7 years STANDARD_DEVIATION 11.7 | 60.9 years STANDARD_DEVIATION 6.6 | 65.8 years STANDARD_DEVIATION 12.1 | 47.5 years STANDARD_DEVIATION 11.1 |
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 4 Participants | 19 Participants | 6 Participants | 3 Participants | 6 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 4 Participants | 11 Participants | 2 Participants | 5 Participants | 0 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| BMI | 27.90 kg/m^2 STANDARD_DEVIATION 4.68 | 27.02 kg/m^2 STANDARD_DEVIATION 3.53 | 26.48 kg/m^2 STANDARD_DEVIATION 1.64 | 26.60 kg/m^2 STANDARD_DEVIATION 3.07 | 27.12 kg/m^2 STANDARD_DEVIATION 4.76 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 30 Participants | 8 Participants | 8 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 30 Participants | 8 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Female | 3 Participants | 9 Participants | 3 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 21 Participants | 5 Participants | 6 Participants | 5 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 | 0 / 8 | 0 / 6 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 0 / 8 | 0 / 6 | 2 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 6 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Concentration-time Curve of Copanlisib in Plasma Over the Time Interval From 0 to 168 h.
AUC(0-168) refers to AUC from time 0 to 168 hr which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment Group | Area Under the Concentration-time Curve of Copanlisib in Plasma Over the Time Interval From 0 to 168 h. | 551.4 μg*h/L | Geometric Coefficient of Variation 53.78 |
| Severe Hepatic Impairment Group | Area Under the Concentration-time Curve of Copanlisib in Plasma Over the Time Interval From 0 to 168 h. | 853.0 μg*h/L | Geometric Coefficient of Variation 26.39 |
| Severe Renal Impairment Group | Area Under the Concentration-time Curve of Copanlisib in Plasma Over the Time Interval From 0 to 168 h. | 350.5 μg*h/L | Geometric Coefficient of Variation 48.55 |
| Healthy Participants | Area Under the Concentration-time Curve of Copanlisib in Plasma Over the Time Interval From 0 to 168 h. | 311.9 μg*h/L | Geometric Coefficient of Variation 23.55 |
Comparison: Moderate Hepatic Impairment group vs Healthy Subjects90% CI: [1.251, 2.498]
Comparison: Severe hepatic impairment group vs Healthy Subjects90% CI: [2.163, 3.459]
Comparison: Severe renal impairment group vs Healthy Subjects90% CI: [0.815, 1.549]
Primary
Area Under the Concentration vs. Time Curve From Zero to Infinity (AUC) of Copanlisib in Plasma.
AUC refers to area under the concentration vs time curve from 0 to infinity which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion
Population: Participants in PK population with available data are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment Group | Area Under the Concentration vs. Time Curve From Zero to Infinity (AUC) of Copanlisib in Plasma. | 594.9 μg*h/L | Geometric Coefficient of Variation 53.85 |
| Severe Hepatic Impairment Group | Area Under the Concentration vs. Time Curve From Zero to Infinity (AUC) of Copanlisib in Plasma. | 940.7 μg*h/L | Geometric Coefficient of Variation 23.7 |
| Severe Renal Impairment Group | Area Under the Concentration vs. Time Curve From Zero to Infinity (AUC) of Copanlisib in Plasma. | 373.7 μg*h/L | Geometric Coefficient of Variation 59.08 |
| Healthy Participants | Area Under the Concentration vs. Time Curve From Zero to Infinity (AUC) of Copanlisib in Plasma. | 347.8 μg*h/L | Geometric Coefficient of Variation 23.99 |
Comparison: Moderate Hepatic Impairment group vs Healthy Subjects90% CI: [1.148, 2.55]
Comparison: Severe hepatic impairment group vs Healthy Subjects90% CI: [2.115, 3.46]
Comparison: Severe renal impairment group vs Healthy Subjects90% CI: [0.696, 1.659]
Primary
Maximum Observed Concentration (Cmax) of Copanlisib in Plasma.
Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment Group | Maximum Observed Concentration (Cmax) of Copanlisib in Plasma. | 68.12 μg/L | Geometric Coefficient of Variation 65.5 |
| Severe Hepatic Impairment Group | Maximum Observed Concentration (Cmax) of Copanlisib in Plasma. | 71.09 μg/L | Geometric Coefficient of Variation 53.9 |
| Severe Renal Impairment Group | Maximum Observed Concentration (Cmax) of Copanlisib in Plasma. | 31.77 μg/L | Geometric Coefficient of Variation 38.25 |
| Healthy Participants | Maximum Observed Concentration (Cmax) of Copanlisib in Plasma. | 49.20 μg/L | Geometric Coefficient of Variation 27.24 |
Comparison: Moderate Hepatic Impairment vs Healthy Subjects90% CI: [0.921, 2.081]
Comparison: Severe hepatic impairment group vs Healthy Subjects90% CI: [0.998, 2.093]
Comparison: Severe renal impairment group vs Healthy Subjects90% CI: [0.486, 0.858]
Secondary
Area Under the Concentration-time Curve of Metabolite M-1 in Plasma Over the Time Interval From 0 to 168 h.
The morpholinone derivative M-1 is a minor copanlisib metabolite in plasma. The PK of metabolite M-1 is routinely analyzed in addition to the PK of the parent compound, although M-1 is not considered to be a major metabolite. AUC from time 0 to 168h which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion
Population: Participants in PK population with available data are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment Group | Area Under the Concentration-time Curve of Metabolite M-1 in Plasma Over the Time Interval From 0 to 168 h. | 82.62 μg*h/L | Geometric Coefficient of Variation 59.06 |
| Severe Hepatic Impairment Group | Area Under the Concentration-time Curve of Metabolite M-1 in Plasma Over the Time Interval From 0 to 168 h. | 83.00 μg*h/L | Geometric Coefficient of Variation 35.34 |
| Severe Renal Impairment Group | Area Under the Concentration-time Curve of Metabolite M-1 in Plasma Over the Time Interval From 0 to 168 h. | 67.12 μg*h/L | Geometric Coefficient of Variation 70.48 |
| Healthy Participants | Area Under the Concentration-time Curve of Metabolite M-1 in Plasma Over the Time Interval From 0 to 168 h. | 74.68 μg*h/L | Geometric Coefficient of Variation 76.75 |
Secondary
Maximum Observed Concentration (Cmax) of Metabolite M-1.
The morpholinone derivative M-1 is a minor copanlisib metabolite in plasma. The PK of metabolite M-1 is routinely analyzed in addition to the PK of the parent compound, although M-1 is not considered to be a major metabolite. Cmax refers to the highest measured drug concentration which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample.
Time frame: before copanlisib administration as well as 10 min and 1 h (end of infusion), 1.5, 2, 2.5, 3, 5, 8, 24, 48, 72, 96, 120 and 168 h after start of infusion
Population: Participants in PK population with available data are reported.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Moderate Hepatic Impairment Group | Maximum Observed Concentration (Cmax) of Metabolite M-1. | 1.868 μg/L | Geometric Coefficient of Variation 53.16 |
| Severe Hepatic Impairment Group | Maximum Observed Concentration (Cmax) of Metabolite M-1. | 1.356 μg/L | Geometric Coefficient of Variation 52.63 |
| Severe Renal Impairment Group | Maximum Observed Concentration (Cmax) of Metabolite M-1. | 1.440 μg/L | Geometric Coefficient of Variation 50.36 |
| Healthy Participants | Maximum Observed Concentration (Cmax) of Metabolite M-1. | 1.543 μg/L | Geometric Coefficient of Variation 47.18 |
Secondary
Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
Adverse events are considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
Time frame: Up to 30 days after end of treatment with study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Adverse events (AE's) | 0 Participants |
| Moderate Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Serious adverse events (SAE's) | 0 Participants |
| Severe Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Serious adverse events (SAE's) | 0 Participants |
| Severe Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Adverse events (AE's) | 0 Participants |
| Severe Renal Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Adverse events (AE's) | 2 Participants |
| Severe Renal Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Serious adverse events (SAE's) | 0 Participants |
| Healthy Participants | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Adverse events (AE's) | 2 Participants |
| Healthy Participants | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | Any Serious adverse events (SAE's) | 0 Participants |
Secondary
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity.
Adverse events are considered to be treatment-emergent if they have started or worsened after first application of study medication up to 30 days after end of treatment with study medication.
Time frame: Up to 30 days after end of treatment with study drug
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Moderate Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Mild | 0 Participants |
| Moderate Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Moderate | 0 Participants |
| Severe Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Moderate | 0 Participants |
| Severe Hepatic Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Mild | 0 Participants |
| Severe Renal Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Mild | 2 Participants |
| Severe Renal Impairment Group | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Moderate | 0 Participants |
| Healthy Participants | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Mild | 1 Participants |
| Healthy Participants | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) in Different Severity. | Moderate | 1 Participants |