Effect of Copanlisib on Metformin Pharmacokinetics and Pharmacodynamics

Study Overview
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Brief Summary
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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.

Official Title
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An Open-label, Non-randomized, Phase I Study to Evaluate the Effect of Copanlisib (a Single Intravenous Dose of 60 mg) on the Pharmacokinetics (PK) and Pharmacodynamics (PD) of Metformin (MATE2-K Substrate) in Healthy Volunteers

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Copanlisib (Aliqopa, BAY80-6946)
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Copanlisib (Aliqopa, BAY80-6946)<br>All subjects will receive a single dose of metformin 1000 mg on Days 1 and 8 in a fasting state. Subjects will also receive a single i.v. dose of 60 mg copanlisib on Day 8 as part of the combination with metformin. | Drug: Copanlisib (Aliqopa, BAY80-6946)<br>* 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.<br>Drug: Metformin<br>* Single dose of 1000 mg is administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8 | 
| 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. | Pre-dose and up to 24 hours after drug administration on Day 1 and Day 8 | 
| 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. | Pre-dose and extrapolated up to infinity after drug administration on Day 1 and Day 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From start of study medication until 30 days after end of treatment with study medication. | 
| 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. | From start of study medication until 30 days after end of treatment with study medication. | 
| 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). | Up to 24 hours after study drug administration on Day 1 and Day 8 | 
| 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. | From pre-dose up to 24 hours after study drug administration on Day 1 and Day 8 |