Healthy
Conditions
Keywords
Concor AM®, Concor®, Norvasc®, Bisoprolol, Amlodipine, Bisoprolol-Amlodipine fixed dose combination, Chinese Participants
Brief summary
This is a Phase I, open-label, randomized, 2-period, 2-sequence, crossover study to demonstrate bioequivalence (BE) between the bisoprolol-amlodipine fixed-dose-combination (FDC) tablet (investigational product) and bisoprolol and amlodipine tablets administered concomitantly (comparators) given as a single oral dose in fasting and fed state.
Interventions
DRUGBisoprolol-Amlodipine FDC
Participants received a single oral dose of 5 milligram(mg)/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) either on Day 1 or Day 15 under fasting or fed conditions.
DRUGBisoprolol
Participants received 5 mg bisoprolol tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.
DRUGAmlodipine
Participants received 5 mg amlodipine tablet as a single oral dose either on Day 1 or Day 15 under fasting or fed conditions.
Sponsors
Merck KGaA, Darmstadt, Germany
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Availability for the entire trial period and willingness to adhere to the protocol requirements as evidenced by the informed consent form (ICF) duly read, signed and dated by the volunteer * Chinese male and female volunteer * Volunteer with a body mass index greater than or equal to 18 and below 28 kilogram/meter\^2 (kg/m\^2) * Systolic blood pressure (in supine position) within 100 to 139 mmHg (inclusive) and diastolic blood pressure (in supine position) within 65 to 90 millimeter of mercury (mmHg) (inclusive) at Screening, during Admission to the Clinical Research Unit (CRU) (12 hour predose) and before each dosing * Clinical laboratory values (within 1 month before screening) within the laboratory's stated normal range; if not within this range, they must lack clinical significance * Healthy according to assessment of the medical history, Electrocardiogram, vital signs, physical examination,laboratory results, negative drug screening, and negative serology tests (except results after vaccination) * Non-smoker or ex-smoker, not using any nicotine product; an ex-smoker being defined as someone who completely stopped smoking for at least 12 months before Day 1 of the trial * Each participant has to be capable of understanding the trial procedures and sign the Informed consent form prior to their participation in the trial * Participants must consent to adhere to the recommended contraceptive methods
Exclusion criteria
* Significant history of hypersensitivity to bisoprolol, amlodipine, other dihydropyridines, or any related products (including excipients of the formulations) * Significant history of severe hypersensitivity reactions (eg, angioedema) to any drugs * Pulse rate (in supine position) less than (\<) 60 beats per minute (bpm) or more than 100 bpm at screening * Presence of significant arrhythmia: QTc interval prolongation (QTc greater than 430 milliseconds (msec), severe sinus node dysfunction, or second or third atrioventricular block * History of low blood pressure (\< 100/65 mmHg) or vegetative dystonia * History or presence of peripheral arterial occlusion or Raynaud's syndrome * Presence of diabetes mellitus * History or presence of asthma * Presence of significant gastrointestinal, liver, kidney disease, surgery, or any other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs or known to potentiate or predispose to undesired effects * Use of any enzyme-modifying drugs, including strong inhibitors of cytochrome P450 (CYP) enzymes (such as cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem, and human immunodeficiency virus \[HIV\] antivirals) and strong inducers of CYP enzymes (such as barbiturates, carbamazepine, glucocorticoids, phenytoin, rifampin, St. John's wort or other herbal medicine known with effect on CYP enzymes) within 28 days before Day 1 of this trial * Presence or history of significant cardiovascular, pulmonary, hematologic, neurologic, endocrine, immunologic, or dermatological disease * Presence or history of significant angina pectoris, acute myocardial infarction or ST segment and T wave changes other than non-clinically significant minor changes * Presence or history of ventricular arrhythmia (such as ventricular tachycardia or ventricular fibrillation) or of congestive heart failure Acute conditions which might alter the renal function (eg, dehydration, severe infection) * Surgery in the previous 28 days before Day 1 of this trial * Any history of tuberculosis and/or prophylaxis for tuberculosis within 10 years of Day 1 of the trial * Positive results to HIV antibody, hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or treponema pallidum (TP) antibody tests * Donation of 50 milliliter (mL) or more of blood within 28 days before Day 1 of the trial; donation of 500 mL or more of blood within 56 days before Day 1 of the trial * History of suicidal tendency, history of or disposition to seizures, state of confusion, clinically relevant psychiatric diseases * Poor motivation, intellectual problems likely to limit the validity of consent to participate in the trial or limit the ability to comply with the protocol requirements or inability to cooperate adequately, inability to understand and to observe the instructions of the physician * Maintenance therapy with any drug, or significant history of drug dependency or alcohol abuse (\> 3 × 14 gram (g) alcohol per day, intake of excessive alcohol, acute or chronic use) * Positive urine screening of drugs of abuse (cannabis, benzodiazepines, barbiturates, opiates, cocaine, and methyl amphetamine), or positive breath test of alcohol * Positive pregnancy test (only for females of child-bearing potential) or females breast feeding a child * Consumption of large quantities of methylxanthine-containing beverages (more than 600 mg caffeine/day: 1 cup (250 mL) of coffee contains approximately 100 mg of caffeine, 1 cup of black or green tea contains approximately 30 mg and 1 glass of cola contains approximately 20 mg caffeine) * Volunteers who took an investigational product (in another clinical trial) by prescription within 2 weeks or an over-the-counter medication taken within 1 week before drug administration
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period | — |
| Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period | AUCextra% was calculated as area under the curve from time tlast extrapolated to infinity given as percentage of AUC 0-infinity. Here, tlast is the last sampling time at which the concentration is at or above the lower limit of quantification. |
| Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period | λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period | — |
| Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period | Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | Baseline up to Day 29 | An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs. |
| Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period | Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. |
| Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period | Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. Terminal half-life was calculated as ln(2)/λz, where λz is a terminal rate constant, which was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve. |
Countries
China
Participant flow
Pre-assignment details
The study was designed to assess bioequivalence (BE) between a single oral dose of bisoprolol-amlodipine fixed-dose-combination (FDC) tablet and bisoprolol and amlodipine, each given concomitantly as a single dose in fasting or fed state.
Participants by arm
| Arm | Count |
|---|---|
| Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately Participants received a single oral dose of 5 milligram(mg)/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 1 in treatment period 1 followed by a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 15 in treatment period 2 under fasting conditions. The two periods were separated by a washout period of 14 days. | 8 |
| Fasting: First Bisoprolol and Amlodipine Separately, Then FDC Participants received a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 1 in treatment period 1 followed by a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 15 in treatment period 2 under fasting conditions. The two periods were separated by a washout period of 14 days. | 8 |
| Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately Participants received a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 1 in treatment period 1 followed by a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 15 in treatment period 2 under fed conditions. The two periods were separated by a washout period of 14 days. | 7 |
| Fed: First Bisoprolol and Amlodipine Separately, Then FDC Participants received a single oral dose of 5 mg bisoprolol and a single oral dose of 5 mg amlodipine given concomitantly on Day 1 in treatment period 1 followed by a single oral dose of 5 mg/5 mg bisoprolol-amlodipine FDC tablet (Concor AM®) on Day 15 in treatment period 2 under fed conditions. The two periods were separated by a washout period of 14 days. | 7 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Treatment Period 1 (8 Days) | Did not pass blood pressure examination | 0 | 0 | 1 | 0 |
| Treatment Period 1 (8 Days) | Protocol non-compliance | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Fasting: First Bisoprolol-Amlodipine FDC, Then Both Separately | Total | Fed: First Bisoprolol and Amlodipine Separately, Then FDC | Fed: First Bisoprolol-Amlodipine FDC, Then Both Separately | Fasting: First Bisoprolol and Amlodipine Separately, Then FDC |
|---|---|---|---|---|---|
| Age, Continuous | 33.9 years STANDARD_DEVIATION 8.89 | 31.6 years STANDARD_DEVIATION 7.01 | 32.4 years STANDARD_DEVIATION 10.29 | 31.0 years STANDARD_DEVIATION 3.56 | 29.3 years STANDARD_DEVIATION 3.15 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 8 Participants | 30 Participants | 7 Participants | 7 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 4 Participants | 11 Participants | 3 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 4 Participants | 19 Participants | 4 Participants | 5 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 0 / 16 | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 0 / 16 | 0 / 16 | 0 / 14 | 0 / 14 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic (PK) Analysis Set included all participants who completed the study with adequate study medication compliance, without any relevant protocol violations with respect to factors likely to affect comparability of PK results, and with sufficient evaluable data to determine primary endpoints (AUC0-t and Cmax ) for both treatments.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Bisoprolol | 294 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 16.7 |
| Fasting: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Amlodipine | 205 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 32.1 |
| Fasting: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Amlodipine | 212 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 34.7 |
| Fasting: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Bisoprolol | 295 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 21.5 |
| Fed: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Bisoprolol | 270 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 23.4 |
| Fed: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Amlodipine | 174 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 29.9 |
| Fed: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Bisoprolol | 275 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 23.9 |
| Fed: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Bisoprolol and Amlodipine | Amlodipine | 167 nanogram hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 33.5 |
Comparison: Statistical Comparison of Bisoprolol in Fasting state90% CI: [93.25, 106.09]
Comparison: Statistical Comparison of Amlodipine in Fasting State90% CI: [92.95, 100.73]
Comparison: Statistical Comparison of Bisoprolol in Fed State90% CI: [90.02, 108.76]
Comparison: Statistical Comparison of Amlodipine in Fed State90% CI: [95.53, 111.2]
Primary
Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Bisoprolol | 26.1 ng/mL | Geometric Coefficient of Variation 20.1 |
| Fasting: Bisoprolol-Amlodipine FDC | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Amlodipine | 4.17 ng/mL | Geometric Coefficient of Variation 25.6 |
| Fasting: Bisoprolol and Amlodipine Separately | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Bisoprolol | 26.6 ng/mL | Geometric Coefficient of Variation 21.2 |
| Fasting: Bisoprolol and Amlodipine Separately | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Amlodipine | 4.17 ng/mL | Geometric Coefficient of Variation 24.1 |
| Fed: Bisoprolol-Amlodipine FDC | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Amlodipine | 3.34 ng/mL | Geometric Coefficient of Variation 23.1 |
| Fed: Bisoprolol-Amlodipine FDC | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Bisoprolol | 20.5 ng/mL | Geometric Coefficient of Variation 18.6 |
| Fed: Bisoprolol and Amlodipine Separately | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Amlodipine | 3.19 ng/mL | Geometric Coefficient of Variation 31.7 |
| Fed: Bisoprolol and Amlodipine Separately | Maximum Observed Plasma Concentration (Cmax) of Bisoprolol and Amlodipine | Bisoprolol | 21.9 ng/mL | Geometric Coefficient of Variation 27.2 |
Comparison: Statistical Comparison of Bisoprolol in Fasting State90% CI: [92.29, 103.74]
Comparison: Statistical Comparison of Amlodipine in Fasting State90% CI: [94.37, 106.03]
Comparison: Statistical Comparison of Bisoprolol in Fed State90% CI: [84.56, 104.2]
Comparison: Statistical Comparison of Amlodipine in Fed State90% CI: [97.82, 116.08]
Secondary
Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine
λz was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression method.
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set. Here, Number Analyzed signified those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Bisoprolol | 0.0781 1 per hour | Geometric Coefficient of Variation 18.1 |
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Amlodipine | 0.0134 1 per hour | Geometric Coefficient of Variation 16.1 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Amlodipine | 0.0139 1 per hour | Geometric Coefficient of Variation 23.5 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Bisoprolol | 0.0784 1 per hour | Geometric Coefficient of Variation 15.4 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Bisoprolol | 0.0731 1 per hour | Geometric Coefficient of Variation 30.2 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Amlodipine | 0.0148 1 per hour | Geometric Coefficient of Variation 16.5 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Bisoprolol | 0.0783 1 per hour | Geometric Coefficient of Variation 20.6 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Terminal Elimination Rate Constant (λz) of Bisoprolol and Amlodipine | Amlodipine | 0.0160 1 per hour | Geometric Coefficient of Variation 26.1 |
Secondary
Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine
Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. Terminal half-life was calculated as ln(2)/λz, where λz is a terminal rate constant, which was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set. Here, Number Analyzed signified those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Bisoprolol | 8.87 hours | Geometric Coefficient of Variation 18.1 |
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Amlodipine | 51.8 hours | Geometric Coefficient of Variation 16.1 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Amlodipine | 49.7 hours | Geometric Coefficient of Variation 23.5 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Bisoprolol | 8.84 hours | Geometric Coefficient of Variation 15.4 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Bisoprolol | 9.49 hours | Geometric Coefficient of Variation 30.2 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Amlodipine | 46.7 hours | Geometric Coefficient of Variation 16.5 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Bisoprolol | 8.86 hours | Geometric Coefficient of Variation 20.6 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Terminal Half-life (t1/2) of Bisoprolol and Amlodipine | Amlodipine | 43.2 hours | Geometric Coefficient of Variation 26.1 |
Secondary
Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine
Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set. Here, Number Analyzed signified those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Bisoprolol | 16.4 liter per hour | Geometric Coefficient of Variation 16.6 |
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Amlodipine | 21.3 liter per hour | Geometric Coefficient of Variation 34.4 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Amlodipine | 23.1 liter per hour | Geometric Coefficient of Variation 31.7 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Bisoprolol | 16.4 liter per hour | Geometric Coefficient of Variation 21.5 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Bisoprolol | 17.8 liter per hour | Geometric Coefficient of Variation 23.4 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Amlodipine | 26.0 liter per hour | Geometric Coefficient of Variation 31.4 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Bisoprolol | 17.4 liter per hour | Geometric Coefficient of Variation 23.2 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Total Body Clearance From Plasma (CL/f) of Bisoprolol and Amlodipine | Amlodipine | 27.4 liter per hour | Geometric Coefficient of Variation 34.8 |
Secondary
Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine
Vz/f is defined as the distribution of a study drug between plasma and the rest of the body after oral dosing.
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set. Here, Number Analyzed signified those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Bisoprolol | 209 liter | Geometric Coefficient of Variation 17 |
| Fasting: Bisoprolol-Amlodipine FDC | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Amlodipine | 1590 liter | Geometric Coefficient of Variation 31 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Amlodipine | 1660 liter | Geometric Coefficient of Variation 40.6 |
| Fasting: Bisoprolol and Amlodipine Separately | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Bisoprolol | 209 liter | Geometric Coefficient of Variation 15.5 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Bisoprolol | 243 liter | Geometric Coefficient of Variation 31.3 |
| Fed: Bisoprolol-Amlodipine FDC | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Amlodipine | 1750 liter | Geometric Coefficient of Variation 30.9 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Bisoprolol | 223 liter | Geometric Coefficient of Variation 19.6 |
| Fed: Bisoprolol and Amlodipine Separately | Apparent Volume of Distribution During the Terminal Phase Following Extravascular Administration (Vz/f) of Bisoprolol and Amlodipine | Amlodipine | 1710 liter | Geometric Coefficient of Variation 40.5 |
Secondary
Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set. Here, Number Analyzed signified those participants who were evaluable for the specified category.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Bisoprolol | 306 ng*h/mL | Geometric Coefficient of Variation 16.6 |
| Fasting: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Amlodipine | 235 ng*h/mL | Geometric Coefficient of Variation 34.4 |
| Fasting: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Amlodipine | 216 ng*h/mL | Geometric Coefficient of Variation 31.7 |
| Fasting: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Bisoprolol | 306 ng*h/mL | Geometric Coefficient of Variation 21.5 |
| Fed: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Bisoprolol | 281 ng*h/mL | Geometric Coefficient of Variation 23.4 |
| Fed: Bisoprolol-Amlodipine FDC | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Amlodipine | 192 ng*h/mL | Geometric Coefficient of Variation 31.4 |
| Fed: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Bisoprolol | 287 ng*h/mL | Geometric Coefficient of Variation 23.2 |
| Fed: Bisoprolol and Amlodipine Separately | Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUC 0-inf) of Bisoprolol and Amlodipine | Amlodipine | 182 ng*h/mL | Geometric Coefficient of Variation 34.8 |
Comparison: Statistical Comparison of Bisoprolol in Fasting State90% CI: [93.61, 106.79]
Comparison: Statistical Comparison of Amlodipine in Fasting State90% CI: [93.38, 104.28]
Comparison: Statistical Comparison of Bisoprolol in Fed State90% CI: [89.75, 108.15]
Comparison: Statistical Comparison of Amlodipine in Fed State90% CI: [96.11, 112.66]
Secondary
Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine
AUCextra% was calculated as area under the curve from time tlast extrapolated to infinity given as percentage of AUC 0-infinity. Here, tlast is the last sampling time at which the concentration is at or above the lower limit of quantification.
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Bisoprolol | 3.60 percentage of AUC0-inf | Geometric Coefficient of Variation 36.1 |
| Fasting: Bisoprolol-Amlodipine FDC | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Amlodipine | 10.9 percentage of AUC0-inf | Geometric Coefficient of Variation 40.1 |
| Fasting: Bisoprolol and Amlodipine Separately | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Amlodipine | 10.8 percentage of AUC0-inf | Geometric Coefficient of Variation 52 |
| Fasting: Bisoprolol and Amlodipine Separately | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Bisoprolol | 3.24 percentage of AUC0-inf | Geometric Coefficient of Variation 25.5 |
| Fed: Bisoprolol-Amlodipine FDC | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Bisoprolol | 3.83 percentage of AUC0-inf | Geometric Coefficient of Variation 21.9 |
| Fed: Bisoprolol-Amlodipine FDC | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Amlodipine | 8.58 percentage of AUC0-inf | Geometric Coefficient of Variation 44.7 |
| Fed: Bisoprolol and Amlodipine Separately | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Bisoprolol | 3.94 percentage of AUC0-inf | Geometric Coefficient of Variation 48.2 |
| Fed: Bisoprolol and Amlodipine Separately | Extrapolated Part of Area Under the Plasma Concentration Curve From Time Zero to Infinity (AUCextra%) of Bisoprolol and Amlodipine | Amlodipine | 6.81 percentage of AUC0-inf | Geometric Coefficient of Variation 64.3 |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation
An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both Serious TEAEs and non-serious TEAEs.
Time frame: Baseline up to Day 29
Population: The Safety Analysis Set included all participants who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | TEAEs | 0 Participants |
| Fasting: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | Serious TEAEs | 0 Participants |
| Fasting: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Fasting: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Death | 0 Participants |
| Fasting: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | Serious TEAEs | 0 Participants |
| Fasting: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Fasting: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | TEAEs | 0 Participants |
| Fasting: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Death | 0 Participants |
| Fed: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Death | 0 Participants |
| Fed: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | TEAEs | 0 Participants |
| Fed: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Fed: Bisoprolol-Amlodipine FDC | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | Serious TEAEs | 0 Participants |
| Fed: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Discontinuation | 0 Participants |
| Fed: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | TEAEs | 0 Participants |
| Fed: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | Serious TEAEs | 0 Participants |
| Fed: Bisoprolol and Amlodipine Separately | Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, AEs Leading to Death, and AEs Leading to Discontinuation | AEs Leading to Death | 0 Participants |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine
Time frame: Pre-dose (Baseline) and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 15, 24, 36, 48, 72, 96, 120, 144 and 168 hours post-dose for each treatment period
Population: The Pharmacokinetic analysis set.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Fasting: Bisoprolol-Amlodipine FDC | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Bisoprolol | 1.00 hours |
| Fasting: Bisoprolol-Amlodipine FDC | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Amlodipine | 6.00 hours |
| Fasting: Bisoprolol and Amlodipine Separately | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Amlodipine | 6.00 hours |
| Fasting: Bisoprolol and Amlodipine Separately | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Bisoprolol | 1.00 hours |
| Fed: Bisoprolol-Amlodipine FDC | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Bisoprolol | 3.00 hours |
| Fed: Bisoprolol-Amlodipine FDC | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Amlodipine | 6.00 hours |
| Fed: Bisoprolol and Amlodipine Separately | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Bisoprolol | 3.00 hours |
| Fed: Bisoprolol and Amlodipine Separately | Time to Reach Maximum Plasma Concentration (Tmax) of Bisoprolol and Amlodipine | Amlodipine | 6.00 hours |
Comparison: Statistical Comparison of Bisoprolol in Fasting State90% CI: [0, 0.5]
Comparison: Statistical Comparison of Amlodipine in Fasting State90% CI: [-1, 0]
Comparison: Statistical Comparison of Bisoprolol in Fed State90% CI: [-1, 0.5]
Comparison: Statistical Comparison of Amlodipine in Fed State90% CI: [-1, 0.5]