Healthy
Conditions
Keywords
Clinical Pharmacology, Drug interaction, Evobrutinib, Digoxin, Metformin, Rosuvastatin, Sumatriptan
Brief summary
This study consisted of 2 parts: Part 1 and 2. The purpose of this study was to evaluate the pharmacokinetic, safety and tolerability of multiple doses of evobrutinib on single doses of digoxin, metformin and rosuvastatin in Part-1 and sumatriptan in Part-2 of the study.
Interventions
DRUGEvobrutinib (45mg)
Participants received film-coated Evobrutinib tablet at a dose of 45 milligrams (mg), orally twice daily on Days 4 to 12 in Part 1 and Days 2 to 8 in Part 2 under fed conditions.
DRUGDigoxin (0.25mg)
Participants received single oral dose of digoxin tablet (0.25 mg) on Day 1 and Day 10 in Part 1 under fed conditions.
DRUGMetformin (10mg)
Participants received single oral dose of metformin 10 mg solution on Day 1 and Day 10 in Part 1 under fed conditions.
DRUGRosuvastatin (10mg)
Participants received single oral dose of rosuvastatin tablet (10 mg) on Day 1 and Day 10 in Part 1 under fed conditions.
DRUGSumatriptan (25mg)
Participants received single dose of sumatriptan tablet (25 mg) on Day 1 and Day 8 in Part 2 under fed conditions.
Sponsors
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
single-sequence study (each part)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Participants were 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 had a body weight within 50.0 and 100.0 kilograms \[kg\] (inclusive) and body mass index within the range of 19.0 and 30.0 kilograms per square meter \[kg/m\^2\] (inclusive) * Other protocol defined inclusion criteria could apply
Exclusion criteria
* 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 * Individuals with diagnosis of hemochromatosis, Wilson´s disease, alpha 1 antitrypsin deficiency, or any other chronic liver disease including Gilbert's disease were excluded from the study * Prior history of cholecystectomy or splenectomy, and any clinically relevant surgery within 6 months prior to Screening * History of any malignancy * 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 * History of shingles within 12 months prior to Screening * History of drug hypersensitivity, ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or formulation ingredients; history of serious allergic reactions leading to hospitalization or any other hypersensitivity reaction in general, which may affect the safety of the participant and/or outcome of the study per the Investigator's discretion * History of alcoholism or drug abuse within 2 years prior to Screening, or positive for drugs of abuse, nicotine/cotinine or alcohol by the laboratory assays conducted during Screening and Day -1 * History of residential exposure to tuberculosis, or a positive QuantiFERON® test within 4 weeks prior to or at the time of Screening * Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to Screening * Moderate or strong inhibitors or inducers of Cytochrome P450, family 3, subfamily A (CYP3A4/5) within 4 weeks prior to the first administration of study intervention * Other protocol defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure. |
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Rosuvastatin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure. |
| Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8 | The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure. |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Digoxin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure. |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Metformin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Rosuvastatin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure. |
| Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8 | Cmax was obtained directly from the concentration versus time curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8 | Tmax was the time to reach the maximum observed concentration collected during a dosing interval. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure. |
| Part 1: Apparent Terminal Half-Life (t1/2) of Digoxin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure. |
| Part 1: Apparent Terminal Half-Life (t1/2) of Metformin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Apparent Terminal Half-Life (t1/2) of Rosuvastatin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure. |
| Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8 | T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure. |
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Digoxin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure. |
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Metformin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Rosuvastatin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure. |
| Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8 | 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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure. |
| Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8 | An adverse event (AE) was 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. Serious AE: 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. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs. |
| Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Metformin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Digoxin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure. |
| Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Metformin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Rosuvastatin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure. |
| Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8 | CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure. |
| Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Rosuvastatin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure. |
| Part 2: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Sumatriptan | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8 | Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure. |
| Part 1: Cumulative Amount Excreted (CAE) From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Metformin | Pre-dose, 0 to 4, 4 to 8, 8 to 12; 12 to 24 hours post-dose on Days 1 and 10 | Ae0-36 was calculated as the cumulative amount excreted from time zero (= dosing time) to the end of the collection interval after dosing, for metformin only. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Renal Clearance (CLr) of Metformin | Pre-dose, 0 to 4, 4 to 8, 8 to 12; 12 to 24 hours post-dose on Days 1 and 10 | CLr was calculated as Ae0-36 divided by AUC0-36, for metformin only. AUC0-36: AUC from time zero (= dosing time) to 36 hours post-dose (metformin only) calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Digoxin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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; Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure. |
| Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8 | Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Participant is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Participant experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the participant is unable to carry out his or her usual activities. Number of participants with TEAEs by severity were reported. |
| Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8 | Laboratory investigation included hematology, biochemistry and urinalysis. Clinical meaningful changes were determined by the investigator. The number of participants with clinically relevant changes from baseline in laboratory parameters were reported. |
| Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8 | Vital signs included body temperature, systolic and diastolic blood pressure and pulse rate. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in vital signs were reported. |
| Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8 | 12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in 12-Lead ECG findings were reported. |
| Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Digoxin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure. |
| Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure. |
| Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Rosuvastatin | Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10 | Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure. |
Countries
Germany
Participant flow
Pre-assignment details
A total of 40 healthy participants were enrolled in two parts single-sequences: Part 1 (Evobrutinib and Cocktail \[digoxin, metformin, and rosuvastatin\] as transporter substrates) and Part 2 (Evobrutinib and Sumatriptan as transporter substrate) with each part consists of 20 participants.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: All Participants Participants received single oral dose of Cocktail (digoxin 0.25 milligrams \[mg\] tablet, metformin 10 mg solution, rosuvastatin 10 mg tablet) on Days 1 and 10; Evobrutinib film-coated tablets at a dose of 45 mg, orally, twice daily on Days 4 to 12 in Part 1 under fed conditions. | 20 |
| Part 2: All Participants Participants received single oral dose of Sumatriptan tablet 25 mg on Days 1 and 8; Evobrutinib film-coated tablets at a dose of 45 mg, orally, twice daily on Days 2 to 8 in Part 2 under fed conditions. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Part 1: All Participants | Part 2: All Participants | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 20 Participants | 20 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 20 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 20 Participants | 40 Participants |
| Sex: Female, Male Female | 11 Participants | 14 Participants | 25 Participants |
| Sex: Female, Male Male | 9 Participants | 6 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 | 0 / 19 | 0 / 20 | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 7 / 20 | 9 / 20 | 6 / 19 | 6 / 20 | 10 / 20 | 8 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 19 | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: Pharmacokinetic (PK) population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin | 15.8 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 21.5 |
| Part 1: Evobrutinib + Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Digoxin | 18.7 Hour*nanogram per milliliter (h*ng/mL) | Geometric Coefficient of Variation 23.7 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [111.89, 125.47]
Primary
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | 20.2 h*ng/mL | Geometric Coefficient of Variation 23.3 |
| Part 1: Evobrutinib + Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Metformin | 42.2 h*ng/mL | Geometric Coefficient of Variation 77.1 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [155.48, 280.82]
Primary
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Rosuvastatin
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Rosuvastatin | 34.6 h*ng/mL | Geometric Coefficient of Variation 64.3 |
| Part 1: Evobrutinib + Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Rosuvastatin | 34.3 h*ng/mL | Geometric Coefficient of Variation 74.7 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [80.49, 121.89]
Primary
Part 1: Maximum Observed Plasma Concentration (Cmax) of Digoxin
Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Maximum Observed Plasma Concentration (Cmax) of Digoxin | 1.15 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 31.7 |
| Part 1: Evobrutinib + Cocktail | Part 1: Maximum Observed Plasma Concentration (Cmax) of Digoxin | 1.15 Nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 34.8 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [85.99, 117.79]
Primary
Part 1: Maximum Observed Plasma Concentration (Cmax) of Metformin
Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Maximum Observed Plasma Concentration (Cmax) of Metformin | 3.24 ng/mL | Geometric Coefficient of Variation 23.1 |
| Part 1: Evobrutinib + Cocktail | Part 1: Maximum Observed Plasma Concentration (Cmax) of Metformin | 6.58 ng/mL | Geometric Coefficient of Variation 76.5 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [152.93, 269.68]
Primary
Part 1: Maximum Observed Plasma Concentration (Cmax) of Rosuvastatin
Cmax was obtained directly from the concentration versus time curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Maximum Observed Plasma Concentration (Cmax) of Rosuvastatin | 2.35 ng/mL | Geometric Coefficient of Variation 60.3 |
| Part 1: Evobrutinib + Cocktail | Part 1: Maximum Observed Plasma Concentration (Cmax) of Rosuvastatin | 2.16 ng/mL | Geometric Coefficient of Variation 66.5 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [76.98, 109.33]
Primary
Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan
The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda z determination: AUC0-inf= AUC0-tlast + Clast pred/lambda z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was defined as the predicted concentration at the last sampling time, calculated from the log-linear regression line for lambda z determination and Lambda z was the apparent terminal rate constant. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan | 52.5 h*ng/mL | Geometric Coefficient of Variation 43.7 |
| Part 1: Evobrutinib + Cocktail | Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Sumatriptan | 46.9 h*ng/mL | Geometric Coefficient of Variation 41 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [82.7, 96.54]
Primary
Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan
Cmax was obtained directly from the concentration versus time curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan | 13.4 ng/mL | Geometric Coefficient of Variation 39.7 |
| Part 1: Evobrutinib + Cocktail | Part 2: Maximum Observed Plasma Concentration (Cmax) of Sumatriptan | 10.9 ng/mL | Geometric Coefficient of Variation 38.6 |
Comparison: Treatment differences on the log scale of transporter substrates with evobrutinib vs substrates alone.90% CI: [74.23, 88.42]
Secondary
Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings
12-lead ECG recordings included rhythm, heart rate (as measured by RR interval), PR interval, QRS duration and QT interval. The corrected QT interval (QTcF) was calculated using Fridericia's formula. 12-lead ECG recordings were obtained after the participants have rested for at least 10 minutes in semisupine position. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in 12-Lead ECG findings were reported.
Time frame: Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8
Population: The SAF included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in 12-Lead Electrocardiogram (ECG) Findings | 0 Participants |
Secondary
Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters
Laboratory investigation included hematology, biochemistry and urinalysis. Clinical meaningful changes were determined by the investigator. The number of participants with clinically relevant changes from baseline in laboratory parameters were reported.
Time frame: Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8
Population: The SAF included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | 0 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Laboratory Parameters | 0 Participants |
Secondary
Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs
Vital signs included body temperature, systolic and diastolic blood pressure and pulse rate. Clinical relevance was determined by the investigator. The number of participants with clinically relevant changes from baseline in vital signs were reported.
Time frame: Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8
Population: The SAF included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | 0 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | 0 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | 0 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Clinically Relevant Changes From Baseline in Vital Signs | 0 Participants |
Secondary
Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) was 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. Serious AE: 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. TEAE: AE with onset after start of treatment or with onset date before the treatment start date but worsening after the treatment start date. TEAEs included both serious and non-serious TEAEs.
Time frame: Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8
Population: The safety analysis set (SAF) included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 7 Participants |
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 9 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 6 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 6 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 10 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 8 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with Serious TEAEs | 0 Participants |
Secondary
Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity
Severity of TEAEs were graded using Qualitative Toxicity Scale, as follows: Mild: Participant is aware of the event or symptom, but the event or symptom is easily tolerated; Moderate: Participant experiences sufficient discomfort to interfere with or reduce his or her usual level of activity; Severe: Significant impairment of functioning: the participant is unable to carry out his or her usual activities. Number of participants with TEAEs by severity were reported.
Time frame: Part 1: Cocktail Alone - Day 1 to Day 3; Evobrutinib Alone - Day 4 to Day 9; Evobrutinib + Cocktail - Day 10 to Day 12; Part 2: Sumatriptan Alone - Day 1; Evobrutinib Alone - Day 2 to Day 7; Evobrutinib + Sumatriptan - Day 8
Population: The SAF included all participants, who were administered any dose of any study intervention.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate TEAEs | 3 Participants |
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Mild TEAEs | 5 Participants |
| Part 1: Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Severe TEAEs | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate TEAEs | 1 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Mild TEAEs | 9 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Severe TEAEs | 0 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate TEAEs | 1 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Mild TEAEs | 6 Participants |
| Part 1: Evobrutinib + Cocktail | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Severe TEAEs | 0 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate TEAEs | 2 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Mild TEAEs | 4 Participants |
| Part 2: Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Severe TEAEs | 0 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate TEAEs | 0 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Mild TEAEs | 10 Participants |
| Part 2: Evobrutinib | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Severe TEAEs | 0 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Mild TEAEs | 7 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Severe TEAEs | 0 Participants |
| Part 2: Evobrutinib + Sumatriptan | Part 1 and Part 2: Number of Participants With Treatment Emergent Adverse Events (TEAEs) by Severity | Moderate TEAEs | 2 Participants |
Secondary
Part 1: Apparent Terminal Half-Life (t1/2) of Digoxin
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Terminal Half-Life (t1/2) of Digoxin | 31.0 Hours |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Terminal Half-Life (t1/2) of Digoxin | 46.9 Hours |
Secondary
Part 1: Apparent Terminal Half-Life (t1/2) of Metformin
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Terminal Half-Life (t1/2) of Metformin | 3.02 Hours |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Terminal Half-Life (t1/2) of Metformin | 3.50 Hours |
Secondary
Part 1: Apparent Terminal Half-Life (t1/2) of Rosuvastatin
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Terminal Half-Life (t1/2) of Rosuvastatin | 15.5 Hours |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Terminal Half-Life (t1/2) of Rosuvastatin | 15.5 Hours |
Secondary
Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Digoxin
CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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; Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLQ) and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Digoxin | 15.9 liter per hour | Geometric Coefficient of Variation 21.5 |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Digoxin | 13.4 liter per hour | Geometric Coefficient of Variation 23.7 |
Secondary
Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Metformin
CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Metformin | 495 liter per hour | Geometric Coefficient of Variation 23.3 |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Metformin | 237 liter per hour | Geometric Coefficient of Variation 77.1 |
Secondary
Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Rosuvastatin
CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Rosuvastatin | 289 liter per hour | Geometric Coefficient of Variation 64.3 |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Total Body Clearance From Plasma (CL/F) of Rosuvastatin | 292 liter per hour | Geometric Coefficient of Variation 74.7 |
Secondary
Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Digoxin
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Digoxin | 787 liters | Geometric Coefficient of Variation 30.6 |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Digoxin | 861 liters | Geometric Coefficient of Variation 34.5 |
Secondary
Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Metformin
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Metformin | 2206 liters | Geometric Coefficient of Variation 33.3 |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Metformin | 1389 liters | Geometric Coefficient of Variation 80.9 |
Secondary
Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Rosuvastatin
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Rosuvastatin | 6712 liters | Geometric Coefficient of Variation 51.5 |
| Part 1: Evobrutinib + Cocktail | Part 1: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Rosuvastatin | 5789 liters | Geometric Coefficient of Variation 68.1 |
Secondary
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Digoxin
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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Digoxin | 12.1 h*ng/mL | Geometric Coefficient of Variation 21.3 |
| Part 1: Evobrutinib + Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Digoxin | 12.9 h*ng/mL | Geometric Coefficient of Variation 23.4 |
90% CI: [102.11, 111.76]
Secondary
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Metformin
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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Metformin | 19.5 h*ng/mL | Geometric Coefficient of Variation 23.7 |
| Part 1: Evobrutinib + Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Metformin | 41.3 h*ng/mL | Geometric Coefficient of Variation 79.2 |
90% CI: [156.34, 285.91]
Secondary
Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Rosuvastatin
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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Rosuvastatin | 31.0 h*ng/mL | Geometric Coefficient of Variation 65 |
| Part 1: Evobrutinib + Cocktail | Part 1: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Rosuvastatin | 30.9 h*ng/mL | Geometric Coefficient of Variation 80.6 |
90% CI: [79.69, 124.42]
Secondary
Part 1: Cumulative Amount Excreted (CAE) From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Metformin
Ae0-36 was calculated as the cumulative amount excreted from time zero (= dosing time) to the end of the collection interval after dosing, for metformin only. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0 to 4, 4 to 8, 8 to 12; 12 to 24 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Cumulative Amount Excreted (CAE) From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Metformin | 0.574 milligrams (mg) | Geometric Coefficient of Variation 37.5 |
| Part 1: Evobrutinib + Cocktail | Part 1: Cumulative Amount Excreted (CAE) From Time Zero to the End of the Collection Interval After Dosing Dosing (Ae0-36) of Metformin | 1.24 milligrams (mg) | Geometric Coefficient of Variation 62.3 |
Secondary
Part 1: Renal Clearance (CLr) of Metformin
CLr was calculated as Ae0-36 divided by AUC0-36, for metformin only. AUC0-36: AUC from time zero (= dosing time) to 36 hours post-dose (metformin only) calculated using the mixed log-linear trapezoidal rule (linear up, log down). The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0 to 4, 4 to 8, 8 to 12; 12 to 24 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 1: Renal Clearance (CLr) of Metformin | 28.5 liter per hour | Geometric Coefficient of Variation 37.9 |
| Part 1: Evobrutinib + Cocktail | Part 1: Renal Clearance (CLr) of Metformin | 29.7 liter per hour | Geometric Coefficient of Variation 26.1 |
Secondary
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Digoxin
Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on digoxin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Digoxin | 1.50 Hours |
| Part 1: Evobrutinib + Cocktail | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Digoxin | 2.00 Hours |
Secondary
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin
Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on metformin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin | 3.00 Hours |
| Part 1: Evobrutinib + Cocktail | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metformin | 4.00 Hours |
Secondary
Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Rosuvastatin
Tmax was the time to reach the maximum observed concentration collected during a dosing interval. The transporter cocktail included digoxin, metformin, and rosuvastatin. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on rosuvastatin in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 10
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Rosuvastatin | 4.00 Hours |
| Part 1: Evobrutinib + Cocktail | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Rosuvastatin | 4.00 Hours |
Secondary
Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan
T1/2 was defined as the time required for the concentration or amount of drug in the body to be reduced by one-half. T1/2 was calculated by natural log 2 divided by Lambda z. Lambda z was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan | 3.16 Hours |
| Part 1: Evobrutinib + Cocktail | Part 2: Apparent Terminal Half-Life (t1/2) of Sumatriptan | 3.56 Hours |
Secondary
Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan
CL/f was calculated as Dose/AUC0-inf, where AUC0-inf was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. AUC0-inf was calculated as AUC0-tlast + Clast pred/Lambda Z, where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clast pred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan | 476 liter per hour | Geometric Coefficient of Variation 43.7 |
| Part 1: Evobrutinib + Cocktail | Part 2: Apparent Total Body Clearance From Plasma (CL/F) of Sumatriptan | 533 liter per hour | Geometric Coefficient of Variation 41 |
Secondary
Part 2: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Sumatriptan
Vz/f: the distribution of a study drug between plasma and the rest of the body after oral dosing. For single dose Vz/f = Dose/(AUC0-inf\*Lambda Z), where AUC0-inf = (AUC0-tlast + Clast pred/Lambda Z), where AUC0-tlast was 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down); Clastpred was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLQ and Lambda Z = the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 2: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Sumatriptan | 2193 liters | Geometric Coefficient of Variation 58.4 |
| Part 1: Evobrutinib + Cocktail | Part 2: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Sumatriptan | 3007 liters | Geometric Coefficient of Variation 46.3 |
Secondary
Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan
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 was calculated using the mixed log-linear trapezoidal rule (linear up, log down). As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Cocktail | Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan | 51.2 h*ng/mL | Geometric Coefficient of Variation 44.4 |
| Part 1: Evobrutinib + Cocktail | Part 2: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time (AUC0-tlast) of Sumatriptan | 45.5 h*ng/mL | Geometric Coefficient of Variation 41.7 |
90% CI: [82.04, 96.19]
Secondary
Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan
Tmax was the time to reach the maximum observed concentration collected during a dosing interval. As pre-specified in protocol, data was analyzed and reported to characterize the effect of evobrutinib on sumatriptan in this outcome measure.
Time frame: Pre-dose, 0.33, 0.67, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 16 hours post-dose on Days 1 and 8
Population: PK population included all participants who have completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results, with adequate study intervention compliance. Here, Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Cocktail | Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan | 2.00 Hours |
| Part 1: Evobrutinib + Cocktail | Part 2: Time to Reach Maximum Plasma Concentration (Tmax) of Sumatriptan | 2.00 Hours |