Healthy Volunteers
Conditions
Brief summary
The purpose of this study is to learn about a drug-drug interaction. When two medications are taken together at the same time, one medication may change the activity of the other medication in the body - this is called a drug-drug interaction. This study is looking at the effect the Bayer study drug, copanlisib, has on metformin, a commonly used medication to treat diabetes. During the study, blood and urine samples will be collected and analyzed to learn about pharmacokinetics (how copanlisib changes metformin levels in the body) and pharmacodynamics (the effect metformin has on the body when taken together with copanlisib) when someone takes both copanlisib and metformin together.
Interventions
The copanlisib dose for this study is the standard dose recently approved and also used in Phase 1, 2 and 3 studies across the copanlisib development program: 60 mg i.v. infusion administered intermittently on Days 1, 8 and 15 of a 28-day cycle. In this study subjects will receive a single i.v. dose of 60 mg copanlisib on day 8.
DRUGMetformin
Single dose of 1000 mg is administered orally.
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects - as determined by the investigator or medically qualified designee based on medical evaluations, including medical history, physical examination, laboratory tests and cardiac monitoring * Aged 18 to 45 years at the first screening visit * Body Mass Index (BMI) of 18.0 - 34 kg / m\*2 , with body weight ≥ 50 kg * Creatinine clearance ≥ 90 mL/min using the Modification of Diet in Renal Disease * Adequate end organ and bone marrow function
Exclusion criteria
* Existing relevant diseases of vital organs (e.g. liver diseases, heart diseases), central nervous system (for example seizures) or other organs (e.g. diabetes mellitus) * Incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, elimination and effects of the study drugs will not be normal * Relevant respiratory insufficiency / disorder * Administration of strong CYP3A4 inhibitors or inducers within 2 weeks prior to dosing * Known history of hypersensitivity (or known allergic reaction) to copanlisib, metformin, related compounds, or any components of the formulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax) | Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8 | Maximum observed drug concentration of metformin in plasma after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured. |
| Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24]) | Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8 | Area under the concentration versus time curve from zero to 24 hours of metformin after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured. |
| Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC) | Pre-dose and extrapolated up to infinity after drug administration on Day 1 and Day 8 | Area under the concentration verus time curve from zero to infinity of metformin after single dose without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events | From start of study medication until 30 days after end of treatment with study medication. | An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication. |
| Maximum Change From Baseline in Plasma Lactate Levels | From pre-dose up to 24 hours after study drug administration on Day 1 and Day 8 | Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Maximum change from baseline on Day 1 and Day 8 was summarized. |
| Number of Participants With Treatment-Emergent Adverse Events by Severity | From start of study medication until 30 days after end of treatment with study medication. | An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication. TEAEs per severity were reported. |
| Plasma Lactate Levels | Up to 24 hours after study drug administration on Day 1 and Day 8 | Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Plasma lactate levels were summarized by treatment conditions (Day 1 and Day 8). |
Countries
United States
Participant flow
Recruitment details
The study was conducted at one study center in the US, between 11-Sep-2018 (first participant first visit) and 12-Nov-2018 (last participant last visit).
Pre-assignment details
A total of 50 participants signed the informed consent form, of them 37 participants were screen failures. The remaining 13 participants received the study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin Participants received 2 oral doses of metformin, 1 dose (1000 milligram \[mg\]) on Day 1 and 1 dose (1000 mg) on Day 8, and a single dose of copanlisib (60 mg, 1 h infusion) on Day 8. A wash-out period of 7 days was maintained between the 2 doses of metformin. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Copanlisib (Aliqopa, BAY80-6946) + Metformin |
|---|---|
| Age, Continuous | 28.4 Years STANDARD_DEVIATION 6.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 7 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 11 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24])
Area under the concentration versus time curve from zero to 24 hours of metformin after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.
Time frame: Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8
Population: Pharmacokinetic Analysis Set (PKS): included all participants with a valid PK profile for metformin.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24]) | Day 1 | 7710 microgram*hour per liter (mcg*h/L) | Geometric Coefficient of Variation 17.6 |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Area Under the Plasma Concentration Versus Time Curve From Zero to 24 Hours of Metformin After Single Dose Administration (AUC[0-24]) | Day 8 | 8640 microgram*hour per liter (mcg*h/L) | Geometric Coefficient of Variation 20.8 |
Comparison: Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of AUC(0-24)90% CI: [1, 1.2555]
Primary
Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC)
Area under the concentration verus time curve from zero to infinity of metformin after single dose without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.
Time frame: Pre-dose and extrapolated up to infinity after drug administration on Day 1 and Day 8
Population: Pharmacokinetic Analysis Set (PKS) with valid data for this evaluation.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC) | Day 1 | 8000 microgram*hour per liter (mcg*h/L) | Geometric Coefficient of Variation 16.9 |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity of Metformin After Single Dose Administration (AUC) | Day 8 | 8900 microgram*hour per liter (mcg*h/L) | Geometric Coefficient of Variation 21.2 |
Comparison: Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of AUC90% CI: [0.9772, 1.2714]
Primary
Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax)
Maximum observed drug concentration of metformin in plasma after single dose administration without copanlisib (Day 1) and in combination with copanlisib (Day 8) were measured.
Time frame: Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8
Population: Pharmacokinetic Analysis Set (PKS): included all participants with a valid PK profile for metformin.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax) | Day 1 | 1550 microgram per liter (mcg/L) | Geometric Coefficient of Variation 16.4 |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Drug Concentration of Metformin in Plasma After Single Dose Administration (Cmax) | Day 8 | 1460 microgram per liter (mcg/L) | Geometric Coefficient of Variation 27.6 |
Comparison: Day 8 (with copanlisib) to Day 1 (without copanlisib) ratio of Cmax90% CI: [0.8093, 1.0931]
Secondary
Maximum Change From Baseline in Plasma Lactate Levels
Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Maximum change from baseline on Day 1 and Day 8 was summarized.
Time frame: From pre-dose up to 24 hours after study drug administration on Day 1 and Day 8
Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (0.5h) | -0.04 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (1h) | 0.05 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (2h) | -0.04 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (4h) | 0.23 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (6h) | -0.03 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (8h) | 0.02 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (12h) | 0.26 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 1 (24h) | 0.12 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (0h) | 0.01 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (0.5h) | 0.07 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (1h) | 0.12 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (2h) | 0.14 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (4h) | 0.44 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (6h) | 0.31 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (8h) | -0.02 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (12h) | 0.13 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Maximum Change From Baseline in Plasma Lactate Levels | Day 8 (24h) | -0.10 mmol/L |
Secondary
Number of Participants With Treatment-Emergent Adverse Events
An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication.
Time frame: From start of study medication until 30 days after end of treatment with study medication.
Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events | Total | 11 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events | Day 1 | 5 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events | Day 8 | 9 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events by Severity
An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse events (TEAEs) were defined as adverse events that started or worsened after the start of study drug administration up to 30 days after last administration of the study medication. TEAEs per severity were reported.
Time frame: From start of study medication until 30 days after end of treatment with study medication.
Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Day 1 | Mild | 5 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Day 1 | Moderate | 0 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Day 1 | No AEs | 8 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Day 8 | Mild | 7 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Day 8 | Moderate | 2 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Day 8 | No AEs | 4 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Total | Mild | 9 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Total | Moderate | 2 Participants |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Number of Participants With Treatment-Emergent Adverse Events by Severity | Total | No AEs | 2 Participants |
Secondary
Plasma Lactate Levels
Lactate levels were analyzed in plasma samples collected during metformin alone or in combination with copanlisib. Plasma lactate levels were summarized by treatment conditions (Day 1 and Day 8).
Time frame: Up to 24 hours after study drug administration on Day 1 and Day 8
Population: Safety Analysis Set (SAF): included all participants who received at least one dose of the study medication.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (0h) | 0.78 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (0.5h) | 0.74 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (1h) | 0.83 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (2h) | 0.74 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (4h) | 1.01 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (6h) | 0.75 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (8h) | 0.80 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (12h) | 1.04 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 1 (24h) | 0.89 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (0h) | 0.78 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (0.5h) | 0.85 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (1h) | 0.90 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (2h) | 0.92 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (4h) | 1.22 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (6h) | 1.08 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (8h) | 0.75 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (12h) | 0.91 mmol/L |
| Copanlisib (Aliqopa, BAY80-6946) + Metformin | Plasma Lactate Levels | Day 8 (24h) | 0.68 mmol/L |