DDI Study of Evobrutinib and Carbamazepine

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all subjects, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

The absolute changes from baseline in Body Temperature (degree Celsius \[°C\]) were reported.

Time frame: Baseline Day 1 and Day 26

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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

Population: The safety analysis set included all participants, who were administered any dose of any study intervention.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

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.

Population: The Pharmacokinetic Analysis Set included all participants who had completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results. Here 'Overall number of participants analyzed' = number of participants evaluable for this outcome measure.