The purpose of this study was to investigate the effect of multiple doses of carbamazepine on two single doses of evobrutinib pharmacokinetics (PK) in healthy participants. Study details included: Study Duration: up to 54 days. Treatment Duration: 25 days. Visit Frequency: Participants were residents in the Clinical Research Unit from Day 1 to Day 20 and returned on Day 26 for a Safety Follow-Up visit.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
14
Participants received a single oral dose of Evobrutinib 45 mg on Day 1 and Day 19
Participants received Carbamazepine 100 mg on Days 2 and 3, 200 mg on Days 4 and 5 and then 300 mg from Days 6 to 19 and were titrated back to 200 mg from Days 20 to 22 and 100 mg on Days 23 to 25 twice daily.
Nuvisan GmbH
Neu-Ulm, Bavaria, Germany
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero Extrapolated to Infinity (AUC0-inf) of Evobrutinib
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.
Maximum Observed Plasma Concentration (Cmax) of Evobrutinib
Cmax was obtained from plasma concentration time curve.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12, 16 and 24 hours post dose on Day 1 and Day 19.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), and Serious TEAEs
An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE's were those events with onset dates on or after the first administration of study intervention. TEAEs include both Serious TEAEs and non-serious TEAEs."
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Hematology Parameter: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values
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Blood samples were collected to analyze the hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes, and Lymphocytes Values. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline was calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Hematology Parameter: Hemoglobin Levels
Blood samples were collected to analyze the hematology parameter: Hemoglobin levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Hematology Parameter: Hematocrit Values
Blood samples were collected to analyze the hematology parameter: Hematocrit Value. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Hematology Parameter: Activated Partial Thromboplastin Time
Blood samples were collected to analyze the hematology parameter: Activated Partial Thromboplastin Time. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Change From Baseline in Hematology Parameters: Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/ Leukocytes, and Neutrophils/Leukocytes
Blood samples were collected to analyze the hematology parameter: basophils/leukocytes, eosinophils/leukocytes, lymphocytes/leukocytes, monocytes/ leukocytes, and neutrophils/leukocytes. The data in terms of 'percentage of cells' was calculated as: Count of Basophils (10\^9 cells/L) (or any other defined hematology parameter e.g. Neutrophils, Eosinophils etc.) divided by the total count of Leukocytes (10\^9 cells/L) in the blood multiplied by 100."
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin
Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume
Blood samples were collected to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Hematology Parameter: Prothrombin International Normalized Ratio
Blood samples were collected to analyze the hematology parameter: Prothrombin International Normalized Ratio. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value. Percent=Fraction×100
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Biochemistry Parameter: Bilirubin, Creatinine and Urate
Blood samples were collected to analyze the Biochemistry Parameter: Bilirubin, Creatinine and Urate. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels
Blood samples were collected to analyze the Biochemistry Parameter: Sodium, Potassium, Calcium, Magnesium and Phosphate Levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Biochemistry Parameter: Protein and Albumin Levels
Blood samples were collected to analyze the Biochemistry Parameter: Protein and Albumin Levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase
Biochemistry Parameter: Alkaline Phosphatase, Amylase, Lipase, Creatinine Kinase, Gamma Glutamyl Transferase Levels, Lactate Dehydrogenase, Aspartate Aminotransferase. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate Levels
Biochemistry Parameter: Glucose, Chloride, Cholesterol, Triglycerides, Phosphate levels. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in 12-Lead ECG Parameter: Heart Rate
12-Lead ECGs were collected after the participants rested quietly for at least 10 minutes in a supine position. 12-Lead ECG Parameter: Heart Rate. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in 12-Lead ECG Parameter: RR Duration, QT Duration, Fridericia's Formula (QTcF), PR Duration and QRS Duration
12-Lead ECGs were collected after the participants rested quietly for at least 10 minutes in a supine position. 12-Lead ECG Parameter: RR Duration. Baseline was the last scheduled measurement before administration of study intervention. Absolute changes from baseline were calculated by subtracting the post-dose visit value from the Baseline value.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Vital Sign: Blood Pressure
Blood pressure (systolic and diastolic) was measured after at least 5 minutes resting, with the participant in the seated position without distractions.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Vital Sign: Pulse Rate
Pulse rate was measured after at least 5 minutes resting, with the subject in the seated position without distractions.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Vital Sign: Respiratory Rate
Respiratory Rate was measured after at least 5 minutes resting, with the participant in the seated position without distractions.
Time frame: Baseline (Day 1) and Day 26
Absolute Change From Baseline in Vital Sign: Body Temperature
The absolute changes from baseline in Body Temperature (degree Celsius \[°C\]) were reported.
Time frame: Baseline Day 1 and Day 26
Total Body Clearance of Evobrutinib From Plasma (CL/f)
CL/f was defined as the apparent total clearance of the drug from plasma after extravascular administration.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.
Apparent Volume of Distribution (Vz/f) of Evobrutinib
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. The apparent volume of distribution during the terminal phase following extravascular administration and was calculated by using the formula=Dose/ (AUC0-inf\* λz).
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-tlast) of Evobrutinib
The AUC from time zero (= dosing time) to the time of the last quantifiable concentration (tlast).
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.
Time to Reach the Maximum Plasma Concentration (Tmax) of Evobrutinib
Tmax was obtained directly from the concentration versus time curve.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.
Apparent Terminal Half-Life (t1/2) of Evobrutinib in Plasma
t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half. Terminal half-life calculated by natural log 2 divided by lambda z.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Evobrutinib Metabolite (MSC2729909A)
AUC0-inf was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast pred/Lambda z, where Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.
Area Under the Plasma Concentration-Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (LOQ) (AUC0-tlast) of Evobrutinib Metabolite (MSC2729909A)
The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration was at or above LOQ. Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.
Maximum Observed Plasma Concentration (Cmax) of Evobrutinib Metabolite (MSC2729909A)
Cmax was obtained from plasma concentration time curve.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.
Time to Reach the Maximum Plasma Concentration (Tmax) of Evobrutinib Metabolite (MSC2729909A)
Tmax was obtained directly from the concentration versus time curve.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.
Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Evobrutinib Metabolite (MSC2729909A) in Plasma
The time prior to the first concentration at or above limit of quantification. It is calculated as last time point at which the concentration is less than (\<) Lower Limit of Quantification (LLOQ) before the occurrence of the first quantifiable concentration.
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.
Metabolite to Parent Ratios for Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of Evobrutinib Metabolite (MSC2729909A)
Molecular weight-corrected ratio of metabolite (M) AUC0-inf to parent (P) AUC0-inf: M/P(AUC0-inf) = (AUC0-inf metabolite (MSC2729909A) \*molecular weight (MW) parent) / (AUC0-inf parent\*MW metabolite (MSC2729909A)).
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12,16 and 24 hours post dose on Day 1 and Day 19.
Metabolite to Parent Ratios for Maximum Observed Plasma Concentration (Cmax) of Evobrutinib Metabolite (MSC2729909A)
Molecular weight-corrected ratio of metabolite Cmax to parent Cmax: M/P(Cmax) = (Cmaxmetabolite (MSC2729909A) \* MWparent) / (Cmax parent \* MW metabolite (MSC2729909A)).
Time frame: Evobrutinib: Predose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8,12,16 and 24 hours post dose on Day 1 and Day 19.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Based on Severity
AE was defined as any untoward medical occurrence in a subject. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. SAE was any untoward medical occurrence that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAE's were those events with onset dates on or after the first administration of study intervention. TEAEs include both Serious TEAEs and non-serious TEAEs. Severity of AE were assessed by the investigator as Mild, Moderate, and Severe: An event that prevents normal everyday activities. Severe is a category used to rate the intensity of an event; both AEs and SAEs can be assessed as severe. SAS is used.
Time frame: Baseline (Day 1) and Day 26