Healthy
Conditions
Brief summary
This trial is to establish bioequivalence of the fixed dose combination (FDC) tablets (containing 12.5 mg empagliflozin/850 mg metformin) (Test, T) compared with the single tablets (10 mg empagliflozin and Glifage® 850 mg tablets) (Reference, R).
Interventions
DRUGFDC 12.5mg empagliflozin/850mg metformin
empagliflozin/metformin
DRUGEmpagliflozin
empagliflozin 10mg (R1)
DRUGGlifage®
Glifage® 850mg (R2)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Masking description
The bioanalytical staff involved are blinded to treatment
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead Electrocardiogram (ECG), and clinical laboratory tests * Age of at least 18 (inclusive) to 50 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 weight divided by height squared (kg/m2) (inclusive) * Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation * Male subjects, or female subjects who meet any of the following criteria from at least 30 days before the first administration of trial medication until 30 days after trial completion: * Use of adequate contraception, e.g. any of the following methods plus condom: * implants, injectables, combined oral or vaginal contraceptives, intrauterine device * Sexually abstinent * A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) * Surgically sterilised (including hysterectomy)
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 millimetre of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 50 to 90 beats per minute (bpm) * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) * History of relevant orthostatic hypotension, fainting spells, or blackouts * Chronic or relevant acute infections * Use of drugs within 30 days of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause time from the start of the Q wave to the end of the T wave (QT) / corrected QT (QTc) interval prolongation) * Smoker (more than 5 cigarettes or 1 cigar or 1 pipe per day) * Detection or indeterminate / inconclusive result of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Coronavirus ribonucleic acid (RNA) in the quantitative real-time polymerase chain reaction (RT-qPCR) exam performed on the day before the admission of each period; * The research participant presents symptoms of coronavirus disease 2019 (COVID-19) infection (even if the result is undetected in the RT-PCR exam for COVID-19) * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 5 minutes (min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) normalized to the actual administered dose is presented. The AUC0-tz was divided by the actual dose strength to get the normalized area under the concentration-time curve. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Unit of measure:(hour\*nanogram/milliliter)/milligram. |
| Dose-normalized Maximum Measured Concentration of Empagliflozin (Cmax) | Within 5 minutes (min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Dose-normalized Maximum measured concentration of empagliflozin in plasma is presented. The maximum measured concentration was divided by the actual dose strength to get the dose-normalised Cmax. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. The unit of measure reported is: (nanogram/milliliter)/milligram. |
| Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. |
| Maximum Measured Concentration of Metformin (Cmax) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Maximum measured concentration of metformin in plasma is presented. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage (%) of the AUC of Empagliflozin That Has Been Derived After Extrapolation | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | The percentage (%) of the AUC of empagliflozin that has been derived after extrapolation is reported. |
| Percentage (%) of the AUC of Metformin That Has Been Derived After Extrapolation | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | The percentage (%) of the AUC of metformin that has been derived after extrapolation is reported. |
| Terminal Half-life of Empagliflozin in Plasma (t1/2) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | The terminal half-life of empagliflozin in plasma (t1/2) is presented. |
| Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞ ) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity from the last quantifiable data point (AUC0-inf) normalized to the actual administered dose is presented. The AUC0-oo was divided by the actual dose strength to get the normalized area under the concentration-time curve. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Unit of measure: (hour\*nanogram/milliliter)/milligram. |
| Elimination Rate Constant (Kel) for Empagliflozin | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | The elimination rate constant (Kel) for empagliflozin is reported. |
| Elimination Rate Constant (Kel) for Metformin | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | The elimination rate constant (Kel) for metformin is reported. |
| Terminal Half-life of Metformin in Plasma (t1/2) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | The terminal half-life of metformin in plasma (t1/2) is presented. |
| Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) is presented. The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. |
| Time From Last Dosing to the Maximum Measured Concentration of Empagliflozin in Plasma (Tmax) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Time from last dosing to the maximum measured concentration of empagliflozin in plasma (tmax) is presented. |
| Time From Last Dosing to the Maximum Measured Concentration of Metformin in Plasma (Tmax) | Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms. | Time from last dosing to the maximum measured concentration of metformin in plasma (tmax) is presented. |
Countries
Brazil
Participant flow
Recruitment details
This was a phase I, randomised, open label, 2x2 crossover trial in healthy male and female subjects to establish the bioequivalence of 1 Fixed dose combination tablet 12.5 mg empagliflozin/850 mg metformin (treatment B) to the reference treatments (treatment A) which consisted in 1 tablet empagliflozin10 mg (Reference 1) + 1 tablet Glifage® 850 mg (Reference 2).
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| (A): Empagliflozin 10mg (R1)+Glifage® 850mg (R2),Then (B): FDC 12.5mg Empagliflozin/850mg Metformin On Day 1 of Period 1 participants received treatment A: Single dose tablet of 10 milligram(mg) empagliflozin film-coated and a 850mg of metformin hydrochloride (HCl) (Glifage®) tablet, orally with 200 milliliter(mL) of water.
On Day 1 of Period 2 participants received treatment B: Fixed dose combination (FDC) tablet of 12.5mg empagliflozin/850 mg metformin HCl, orally with 200mL of water.
A high-fat, high-calorie meal was served 30 minutes(min) before drug administration. The treatments were separated by a wash-out phase of at least 7 days. | 16 |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin,Then (A): Empagliflozin 10mg(R1) + Glifage® 850mg(R2) On Day 1 of Period 1 participants received treatment B: Fixed dose combination (FDC) tablet containing 12.5 milligram (mg) empagliflozin/850 mg metformin hydrochloride (HCl), orally with 200 milliliter (mL) of water.
On Day 1 of Period 2 participants received treatment A: Single dose tablet of 10mg empagliflozin and 850 mg of metformin HCl (Glifage®) tablet, orally with 200mL of water.
A high-fat, high-calorie meal was served 30 minutes (min) before drug administration. The treatments were separated by a wash-out phase of at least 7 days. | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Adverse Event | 1 | 1 |
| Period 1 | Positive doping for Tetrahydrocannabinol (THC) | 2 | 1 |
| Period 2 | Adverse Event | 0 | 2 |
| Period 2 | The patient was not able to eat the full content of the breakfast | 1 | 0 |
Baseline characteristics
| Characteristic | (B): FDC 12.5mg Empagliflozin/850mg Metformin,Then (A): Empagliflozin 10mg(R1) + Glifage® 850mg(R2) | Total | (A): Empagliflozin 10mg (R1)+Glifage® 850mg (R2),Then (B): FDC 12.5mg Empagliflozin/850mg Metformin |
|---|---|---|---|
| Age, Continuous | 31.7 Years STANDARD_DEVIATION 8.3 | 31.8 Years STANDARD_DEVIATION 7.9 | 32.0 Years STANDARD_DEVIATION 7.2 |
| 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 | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 9 Participants | 6 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 | 11 Participants | 18 Participants | 7 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 29 |
| other Total, other adverse events | 5 / 30 | 2 / 29 |
| serious Total, serious adverse events | 0 / 30 | 0 / 29 |
Outcome results
Primary
Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of metformin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is presented. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 10299.45 hour*nanogram/milliliter (h*ng/mL) |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 10467.41 hour*nanogram/milliliter (h*ng/mL) |
Comparison: The statistical model used for the analysis of the was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.p-value: 0.47190% CI: [97.85, 105.55]ANOVA
Primary
Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) normalized to the actual administered dose is presented. The AUC0-tz was divided by the actual dose strength to get the normalized area under the concentration-time curve. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Unit of measure:(hour\*nanogram/milliliter)/milligram.
Time frame: Within 5 minutes (min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 117.15 (h*ng/mL)/mg |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 116.65 (h*ng/mL)/mg |
Comparison: The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.p-value: 0.779290% CI: [97.03, 102.19]ANOVA
Primary
Dose-normalized Maximum Measured Concentration of Empagliflozin (Cmax)
Dose-normalized Maximum measured concentration of empagliflozin in plasma is presented. The maximum measured concentration was divided by the actual dose strength to get the dose-normalised Cmax. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. The unit of measure reported is: (nanogram/milliliter)/milligram.
Time frame: Within 5 minutes (min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Dose-normalized Maximum Measured Concentration of Empagliflozin (Cmax) | 13.42 (ng/mL)/mg |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Dose-normalized Maximum Measured Concentration of Empagliflozin (Cmax) | 13.60 (ng/mL)/mg |
Comparison: The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.p-value: 0.649390% CI: [96.39, 106.59]ANOVA
Primary
Maximum Measured Concentration of Metformin (Cmax)
Maximum measured concentration of metformin in plasma is presented. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Maximum Measured Concentration of Metformin (Cmax) | 1333.58 nanogram/milliliter (ng/mL ) |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Maximum Measured Concentration of Metformin (Cmax) | 1308.39 nanogram/milliliter (ng/mL ) |
Comparison: The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.p-value: 0.425190% CI: [94.24, 102.15]ANOVA
Secondary
Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) is presented. The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 10440.79 hour*nanogram/milliliter (hr*ng/mL) |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 10570.45 hour*nanogram/milliliter (hr*ng/mL) |
Comparison: The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.p-value: 0.589590% CI: [97.4, 105.24]ANOVA
Secondary
Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞ )
Area under the concentration-time curve of empagliflozin in plasma over the time interval from 0 extrapolated to infinity from the last quantifiable data point (AUC0-inf) normalized to the actual administered dose is presented. The AUC0-oo was divided by the actual dose strength to get the normalized area under the concentration-time curve. The statistical model used for the analysis of the primary endpoints was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. Unit of measure: (hour\*nanogram/milliliter)/milligram.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞ ) | 118.25 (h*ng/mL)/mg |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Dose-normalized Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞ ) | 117.64 (h*ng/mL)/mg |
Comparison: The statistical model used for the analysis was an analysis of variance (ANOVA) on the logarithmic scale. That is, the PK endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.p-value: 0.737990% CI: [96.93, 102.11]ANOVA
Secondary
Elimination Rate Constant (Kel) for Empagliflozin
The elimination rate constant (Kel) for empagliflozin is reported.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Elimination Rate Constant (Kel) for Empagliflozin | 0.93 1/hours (1/hr) | Standard Deviation 0.61 |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Elimination Rate Constant (Kel) for Empagliflozin | 0.84 1/hours (1/hr) | Standard Deviation 0.44 |
Secondary
Elimination Rate Constant (Kel) for Metformin
The elimination rate constant (Kel) for metformin is reported.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Elimination Rate Constant (Kel) for Metformin | 1.33 1/hours (1/hr) | Standard Deviation 2.14 |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Elimination Rate Constant (Kel) for Metformin | 0.97 1/hours (1/hr) | Standard Deviation 1.02 |
Secondary
Percentage (%) of the AUC of Empagliflozin That Has Been Derived After Extrapolation
The percentage (%) of the AUC of empagliflozin that has been derived after extrapolation is reported.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Percentage (%) of the AUC of Empagliflozin That Has Been Derived After Extrapolation | 9.77 Percentage (%) | Standard Deviation 3.04 |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Percentage (%) of the AUC of Empagliflozin That Has Been Derived After Extrapolation | 9.31 Percentage (%) | Standard Deviation 1.87 |
Secondary
Percentage (%) of the AUC of Metformin That Has Been Derived After Extrapolation
The percentage (%) of the AUC of metformin that has been derived after extrapolation is reported.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Percentage (%) of the AUC of Metformin That Has Been Derived After Extrapolation | 14.35 Percentage (%) | Standard Deviation 8.5 |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Percentage (%) of the AUC of Metformin That Has Been Derived After Extrapolation | 13.04 Percentage (%) | Standard Deviation 5.58 |
Secondary
Terminal Half-life of Empagliflozin in Plasma (t1/2)
The terminal half-life of empagliflozin in plasma (t1/2) is presented.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Terminal Half-life of Empagliflozin in Plasma (t1/2) | 0.08 Hours (hr) |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Terminal Half-life of Empagliflozin in Plasma (t1/2) | 0.08 Hours (hr) |
Secondary
Terminal Half-life of Metformin in Plasma (t1/2)
The terminal half-life of metformin in plasma (t1/2) is presented.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Terminal Half-life of Metformin in Plasma (t1/2) | 0.06 Hours (hr) |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Terminal Half-life of Metformin in Plasma (t1/2) | 0.06 Hours (hr) |
Secondary
Time From Last Dosing to the Maximum Measured Concentration of Empagliflozin in Plasma (Tmax)
Time from last dosing to the maximum measured concentration of empagliflozin in plasma (tmax) is presented.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Time From Last Dosing to the Maximum Measured Concentration of Empagliflozin in Plasma (Tmax) | 2.33 Hours (hr) |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Time From Last Dosing to the Maximum Measured Concentration of Empagliflozin in Plasma (Tmax) | 2.17 Hours (hr) |
Secondary
Time From Last Dosing to the Maximum Measured Concentration of Metformin in Plasma (Tmax)
Time from last dosing to the maximum measured concentration of metformin in plasma (tmax) is presented.
Time frame: Within 5 minutes(min) before and 15min, 30min, 45min, 1h, 1h15min, 1h30min, 1h45min, 2h, 2h20min, 2h40min, 3h, 3h30min, 4h, 4h30min, 5h, 5h30min, 6h, 7h, 8h, 10h, 12h, 24h, 48h, and 72h after treatment administration for both arms.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This set included all subjects who provided all PK endpoints for all treatment periods that were defined as primary (Cmax and AUCo-tz) and was not excluded due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability. Only subjects with non-missing values were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| (A): Empagliflozin 10mg (R1) + Metformin (Glifage®) 850mg (R2) | Time From Last Dosing to the Maximum Measured Concentration of Metformin in Plasma (Tmax) | 4.00 Hours (hr) |
| (B): FDC 12.5mg Empagliflozin/850mg Metformin | Time From Last Dosing to the Maximum Measured Concentration of Metformin in Plasma (Tmax) | 4.00 Hours (hr) |