Effect of Evobrutinib on Pharmacokinetics of a Combined Oral Contraceptive

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 serum concentration at the last sampling time point at which the measured serum concentration is at or above the Lower Limit of quantification (LLOQ) and Lambda z was the apparent terminal rate constant determined by log-linear regression analysis of the measured serum concentrations of the terminal log-linear phase.

Cmax was obtained directly from the concentration versus time curve.

An adverse event (AE) is defined as any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether considered related to the study intervention or not. A serious AE was an AE 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. TEAEs were defined as events with onset date or worsening during the on-treatment period. TEAEs included both serious and non-serious TEAEs.

The Investigator assessed the severity of each AE and SAE reported during the study and assign it to one of the following categories: Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not interfering with everyday activities; Moderate: An event that causes sufficient discomfort and interferes with normal everyday activities; Severe: An event that prevents normal everyday activities. Do not confuse an AE that is assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; both AEs and SAEs can be assessed as severe.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: hemoglobin.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the coagulation parameter: Activated Partial Thromboplastin Time.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Hemoglobin.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the hematology parameter: Erythrocytes Mean Corpuscular Volume.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the coagulation parameter: Prothrombin Intl. Normalized Ratio.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: bilirubin, creatinine and urate.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: Total Protein.

Blood samples were collected in a fasted condition (after a fast of at least 12 hours) to analyze the chemistry parameter: C Reactive Protein.

Diastolic blood pressure and systolic blood pressure were measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.

Pulse rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.

Respiratory rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.

Temperature was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.

Heart rate was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions

RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration was measured after at least 5 minutes of rest for the participant in a quiet sitting without distractions.

Time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

Terminal half-life was calculated as log2 divided by lambda z. Lambda z was terminal elimination rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ). Calculated using the mixed log-linear trapezoidal rule (linear up, log down).

Apparent total body clearance of drug from plasma following extravascular administration, calculated as dose/AUC0-infinity for Ethinyl Estradiol/Norethisterone.

Vz/f is defined as the apparent volume of distribution during the terminal phase following extravascular administration for Ethinyl Estradiol/Norethisterone.