Effect of Evobrutinib on Pharmacokinetics of a Combined Oral Contraceptive

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany20 enrolled

Overview

The purpose of this study was to assess the effect of M2951 on the pharmacokinetics (PK) of a combined oral contraceptive \[Ethinyl estradiol/Norethisterone (EE/NET)\] in healthy female participants. * Study Duration: up to 46 days * Treatment Duration: Days 4 to 17 (14 days treatment with M2951); Days 1 and 15 (2 days treatment with Combined Oral Contraceptive \[COC\]) * Visit Frequency: Participants were resident in the Clinical Research Unit from Day -1 to Day 18.

Study Type

INTERVENTIONAL

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Healthy

Interventions

EvobruitnibDRUG

Participants received Evobruitnib at a dose of 45 mg orally twice daily on Days 4 to 17.

Combined oral contraceptive [ethinyl estradiol/ norethisterone (EE/NET)]DRUG

Participants received combined oral contraceptive (COC) \[0.03 milligrams (mg) of Ethinyl Estradiol (EE)\], 0.5 mg of Norethisterone (NET)\] orally on Day 1 and 15.

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 68 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants are overtly healthy as determined by medical evaluation, including no clinically significant abnormality identified on physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion * Participants have a body weight within 50.0 and 100.0 kilograms (kg) (inclusive) and body mass index within the range 19.0 and 30.0 kilograms per square meter (kg/m\^2) (inclusive) * Participants are nonsmokers for at least 6 months preceding Screening * Female participants who are not a Woman of Childbearing Potential (WOCBP) * Other protocol defined inclusion criteria could apply Exclusion Criteria: * Participants with history or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation * Participants with diagnosis of hemochromatosis, Wilson´s disease, alpha 1 antitrypsin deficiency, or any other chronic liver disease including Gilbert's disease will be excluded from the study * Participants with prior history of splenectomy or any clinically relevant surgery within 3 months prior to Screening * Participants with history of any malignancy * Participants with history of chronic or recurrent acute infection or any bacterial, viral, parasitic, or fungal infections within 30 days prior to Screening and at any time between Screening and admission, or hospitalization due to infection within 6 months prior to Screening * Participants with history of shingles within 12 months prior to Screening * Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to Screening. Administration of other types of vaccines \[e.g., Severe acute respiratory syndrome coronavirus 2 (SARSCoV2) vaccines\] is allowed until 4 weeks before admission to CRU, thereafter it is prohibited until the end of the study * Note: In case of clinical symptoms, the participant should be symptom-free for at least 1 week prior to admission to Clinical Research Unit (CRU) * Other protocol defined exclusion criteria could apply

Locations (1)

Nuvisan GmbH

Neu-Ulm, Germany

Outcomes

Primary Outcomes

Area Under the Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Ethinyl Estradiol and Norethisterone

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.

Time frame: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Maximum Observed Plasma Concentration (Cmax) of Ethinyl Estradiol and Norethisterone

Cmax was obtained directly from the concentration versus time curve.

Time frame: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Secondary Outcomes

Number of Participants With Treatment- Emergent Adverse Events (TEAEs)

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.

Time frame: Up to 46 days

Number of Participants With Treatment- Emergent Adverse Events (TEAEs) by Severity

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.

Data from ClinicalTrials.gov

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Time frame: Up to 46 days

Change From Baseline in Hematology Parameter: Hemoglobin at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Hematology Parameter: Erythrocytes at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Hematology Parameters: Platelets, Leukocytes, Neutrophils, Eosinophils, Basophils, Monocytes and Lymphocytes at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Hematology Parameters: Hematocrit, Basophils/Leukocytes, Eosinophils/Leukocytes, Lymphocytes/Leukocytes, Monocytes/Leukocytes and Neutrophils/Leukocytes at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Coagulation Parameter: Activated Partial Thromboplastin Time at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Hemoglobin at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Hematology Parameter: Erythrocytes Mean Corpuscular Volume at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Coagulation Parameter: Prothrombin Intl. Normalized Ratio at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Chemistry Parameters: Bilirubin, Creatinine and Urate at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Chemistry Parameters: Aspartate Aminotransferase, Alanine Aminotransferase, Alkaline Phosphatase, Amylase, Lipase, Gamma Glutamyl Transferase and Lactate Dehydrogenase at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Chemistry Parameters: Sodium, Potassium, Calcium, Glucose, Chloride and Triglycerides at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Chemistry Parameters: Total Protein at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Chemistry Parameters: C Reactive Protein at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Vital Signs: Systolic Blood Pressure and Diastolic Blood Pressure at Day 18

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.

Time frame: Baseline, Day 18

Change From Baseline in Vital Signs: Pulse Rate at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Vital Signs: Respiratory Rate at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Vital Signs: Temperature at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Electrocardiograms (ECGs) Parameter: Heart Rate at Day 18

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

Time frame: Baseline, Day 18

Change From Baseline in Electrocardiograms (ECGs) Parameter: RR Duration, QT Duration, QTcF Duration, PR Duration, QRS Duration at Day 18

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 frame: Baseline, Day 18

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Ethinyl Estradiol and Norethisterone

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

Time frame: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Terminal Half Life (T1/2) of Ethinyl Estradiol and Norethisterone

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.

Time frame: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Area Under the Plasma Concentration Time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUC0-t) of Ethinyl Estradiol and Norethisterone

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).

Time frame: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Apparent Total Body Clearance (CL/f) of Ethinyl Estradiol and Norethisterone

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

Time frame: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18

Apparent Volume of Distribution During Terminal Phase (VZ/f) of Ethinyl Estradiol and Norethisterone

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

Time frame: Pre-dose, 0.3, 0.6, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60 and 72 hours post-dose on Days 1, 2, 3, 4, 15, 16, 17 and 18