Healthy
Conditions
Brief summary
The purpose of this trial is to demonstrate the relative bioavailability of 2 newly developed fixed dose combinations (FDC) tablets containing empagliflozin, linagliptin & metformin extended release (XR) and the single tablets of empagliflozin, linagliptin and metformin XR administered simultaneously.
Interventions
DRUGHigh dose FDC Empagliflozin/Linagliptin/Metformin XR, fed
High dose Empagliflozin/Linagliptin/Metformin extended release (XR) fixed dose combination (FDC) tablet
DRUG1 tab Empagliflozin +1 tab Linagliptin +2 tabs Metformin XR
1x Empagliflozin + 1x Linagliptin + 2x Metformin extended release (XR) tablets
DRUGHigh dose FDC Empagliflozin/Linagliptin/Metformin XR, fasted
High dose Empagliflozin/Linagliptin/Metformin extended release (XR) fixed dose combination (FDC) tablet
DRUGLow dose FDC Empagliflozin/Linagliptin/Metformin XR, fed
Low dose Empagliflozin/Linagliptin/Metformin extended release (XR) fixed dose combination (FDC) tablet
Sponsors
Eli Lilly and Company
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects according to the investigator's assessment, based on a complete medical history including a physical examination, vital signs (blood pressure, pulse rate), 12-lead electrocardiogram, and clinical laboratory tests * Age of 18 to 55 years (incl.) * BMI of 18.5 to 29.9 kg/m2 (incl.) * Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation * Male subjects, or female subjects who meet any of the following criteria starting from at least 30 days before the first administration of trial medication and 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) Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of follicle-stimulating hormone above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including blood pressure, pulse rate or electrocardiogram) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours (AUC0-72) is presented |
| Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Maximum measured concentration of Empagliflozin in plasma (Cmax) is presented |
| Maximum Measured Concentration of Metformin in Plasma (Cmax) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Maximum measured concentration of Metformin in plasma (Cmax) is presented |
| Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Maximum measured concentration of Linagliptin in plasma (Cmax) is presented |
| Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) is presented. Plasma concentrations and/or parameters of a subject were considered as non-evaluable, if for example * The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subject's experiencing emesis) * A pre-dose concentration was \>5% of the Cmax value measured in that subject * Missing samples or concentration data at important phases of PK disposition curve |
| Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Area under the concentration-time curve of Metformin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) is presented |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Area under the concentration-time curve of the Metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented |
| Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Area under the concentration-time curve of the Linagliptin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented |
| Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration | Area under the concentration-time curve of the Empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented |
Countries
Germany
Participant flow
Pre-assignment details
The subjects were randomly allocated to the 2 treatment sequences (test (T) - reference (R) or R-T) in 3 separate trial parts. There was a wash-out period of at least 35 days between the treatments.Treatments were administered as single doses in the fed state in Parts 1 and 3, and in the fasted state in Part 2.
Participants by arm
| Arm | Count |
|---|---|
| FDC 25 Fed (T1)/ E25+L5+M1000 Fed (R1) (Part 1) Subjects were orally administered single dose of 25 milligram (mg) empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 millilitre (mL) of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast | 7 |
| E25+L5+M1000 Fed (R1)/ FDC 25 Fed (T1) (Part 1) Subjects were orally administered free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast | 8 |
| FDC 25 Fast (T2)/ E25+L5+M1000 Fast (R2) (Part 2) Subjects were orally administered single dose of 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after an overnight fast of at least 10 h followed by a wash-out period of at least 35 days and then orally administered free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after an overnight fast of at least 10 h | 10 |
| E25+L5+M1000 Fast (R2)/ FDC 25 Fast (T2) (Part 2) Subjects were orally administered single dose of free combination of 25 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after an overnight fast of at least 10 h followed by a wash-out period of at least 35 days and then orally administered 25 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after an overnight fast of at least 10 h | 10 |
| FDC 10 Fed (T3)/ E10+L5+M1000 Fed (R3) (Part 3) Subjects were orally administered single dose of 10 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered free combination of 10 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast | 7 |
| E10+L5+M1000 Fed (R3)/ FDC 10 Fed (T3) (Part 3) Subjects were orally administered free combination of 10 mg empagliflozin, 5 mg linagliptin and 2 times 500 mg metformin extended release tablets with 240 mL of water after a high-fat, high-calorie breakfast followed by a wash-out period of at least 35 days and then orally administered single dose of 10 mg empagliflozin/5 mg linagliptin/1000 mg metformin extended release (XR) fixed dose combination (FDC) tablet with 240 mL of water after a high-fat, high-calorie breakfast | 8 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Other than specified | 1 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | FDC 25 Fed (T1)/ E25+L5+M1000 Fed (R1) (Part 1) | E25+L5+M1000 Fed (R1)/ FDC 25 Fed (T1) (Part 1) | FDC 25 Fast (T2)/ E25+L5+M1000 Fast (R2) (Part 2) | E25+L5+M1000 Fast (R2)/ FDC 25 Fast (T2) (Part 2) | FDC 10 Fed (T3)/ E10+L5+M1000 Fed (R3) (Part 3) | E10+L5+M1000 Fed (R3)/ FDC 10 Fed (T3) (Part 3) | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 36.7 years STANDARD_DEVIATION 8.9 | 37.1 years STANDARD_DEVIATION 11.9 | 36.2 years STANDARD_DEVIATION 12.3 | 34.1 years STANDARD_DEVIATION 10 | 37.3 years STANDARD_DEVIATION 11.9 | 35.3 years STANDARD_DEVIATION 9.4 | 36.0 years STANDARD_DEVIATION 10.4 |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants | 2 Participants | 4 Participants | 1 Participants | 21 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 8 Participants | 3 Participants | 7 Participants | 29 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 | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 15 | 4 / 14 | 6 / 20 | 4 / 18 | 1 / 14 | 4 / 15 |
| serious Total, serious adverse events | 0 / 15 | 0 / 14 | 0 / 20 | 0 / 18 | 0 / 14 | 0 / 15 |
Outcome results
Primary
Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz)
Area under the concentration-time curve of Empagliflozin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) is presented. Plasma concentrations and/or parameters of a subject were considered as non-evaluable, if for example * The subject experienced emesis that occurred at or before 2 times median tmax of the respective treatment (median tmax was to be determined excluding the subject's experiencing emesis) * A pre-dose concentration was \>5% of the Cmax value measured in that subject * Missing samples or concentration data at important phases of PK disposition curve
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: Pharmacokinetic (PK) parameter analysis set (PKS): This subject set included all subjects in the TS who provided at least 1 primary or secondary PK parameter that was not excluded according to the criterion's for non-evaluable above.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 5990 nanomoles (nmol)*hours (h)/litres (L) | Geometric Coefficient of Variation 25.6 |
| E25+L5+M1000 Fed (R1) | Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 6120 nanomoles (nmol)*hours (h)/litres (L) | Geometric Coefficient of Variation 22.8 |
| FDC 25 Fast (T2) | Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 6430 nanomoles (nmol)*hours (h)/litres (L) | Geometric Coefficient of Variation 20.2 |
| E25+L5+M1000 Fast (R2) | Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 6250 nanomoles (nmol)*hours (h)/litres (L) | Geometric Coefficient of Variation 18.7 |
| FDC 10 Fed (T3) | Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 2080 nanomoles (nmol)*hours (h)/litres (L) | Geometric Coefficient of Variation 15.4 |
| E10+L5+M1000 Fed (R3) | Area Under the Concentration-time Curve of Empagliflozin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 2130 nanomoles (nmol)*hours (h)/litres (L) | Geometric Coefficient of Variation 15.5 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [92.89, 100.66]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [97.99, 103.7]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [95.96, 103.85]
Primary
Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72)
Area under the concentration-time curve of Linagliptin in plasma over the time interval from 0 to 72 hours (AUC0-72) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 273 nmol*h/L | Geometric Coefficient of Variation 18.7 |
| E25+L5+M1000 Fed (R1) | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 282 nmol*h/L | Geometric Coefficient of Variation 17.2 |
| FDC 25 Fast (T2) | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 290 nmol*h/L | Geometric Coefficient of Variation 24.7 |
| E25+L5+M1000 Fast (R2) | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 276 nmol*h/L | Geometric Coefficient of Variation 21.1 |
| FDC 10 Fed (T3) | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 258 nmol*h/L | Geometric Coefficient of Variation 25.1 |
| E10+L5+M1000 Fed (R3) | Area Under the Concentration-time Curve of Linagliptin in Plasma Over the Time Interval From 0 to 72 Hours (AUC0-72) | 260 nmol*h/L | Geometric Coefficient of Variation 20.2 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [92.13, 100.75]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [99.95, 110.45]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [96.41, 104.38]
Primary
Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz)
Area under the concentration-time curve of Metformin in plasma over the time interval from 0 to the time of the last quantifiable concentration (AUC0-tz) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 13900 nanograms (ng)*h/ milliliter (mL) | Geometric Coefficient of Variation 29.6 |
| E25+L5+M1000 Fed (R1) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 13900 nanograms (ng)*h/ milliliter (mL) | Geometric Coefficient of Variation 30.9 |
| FDC 25 Fast (T2) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 7920 nanograms (ng)*h/ milliliter (mL) | Geometric Coefficient of Variation 31.3 |
| E25+L5+M1000 Fast (R2) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 8260 nanograms (ng)*h/ milliliter (mL) | Geometric Coefficient of Variation 33.4 |
| FDC 10 Fed (T3) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 12000 nanograms (ng)*h/ milliliter (mL) | Geometric Coefficient of Variation 26 |
| E10+L5+M1000 Fed (R3) | Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Time of the Last Quantifiable Concentration (AUC0-tz) | 12200 nanograms (ng)*h/ milliliter (mL) | Geometric Coefficient of Variation 25.9 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [90.65, 103.42]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [87.44, 104.68]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [92.12, 105.25]
Primary
Maximum Measured Concentration of Empagliflozin in Plasma (Cmax)
Maximum measured concentration of Empagliflozin in plasma (Cmax) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | 594 nmol/L | Geometric Coefficient of Variation 17.7 |
| E25+L5+M1000 Fed (R1) | Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | 630 nmol/L | Geometric Coefficient of Variation 20.4 |
| FDC 25 Fast (T2) | Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | 872 nmol/L | Geometric Coefficient of Variation 24.5 |
| E25+L5+M1000 Fast (R2) | Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | 817 nmol/L | Geometric Coefficient of Variation 31.5 |
| FDC 10 Fed (T3) | Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | 232 nmol/L | Geometric Coefficient of Variation 20.5 |
| E10+L5+M1000 Fed (R3) | Maximum Measured Concentration of Empagliflozin in Plasma (Cmax) | 235 nmol/L | Geometric Coefficient of Variation 18.8 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [86.6, 104.08]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [100.65, 112.96]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [94.54, 106.64]
Primary
Maximum Measured Concentration of Linagliptin in Plasma (Cmax)
Maximum measured concentration of Linagliptin in plasma (Cmax) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 6.37 nmol/L | Geometric Coefficient of Variation 20.6 |
| E25+L5+M1000 Fed (R1) | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 6.51 nmol/L | Geometric Coefficient of Variation 19.4 |
| FDC 25 Fast (T2) | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 9.66 nmol/L | Geometric Coefficient of Variation 44.5 |
| E25+L5+M1000 Fast (R2) | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 8.35 nmol/L | Geometric Coefficient of Variation 27.2 |
| FDC 10 Fed (T3) | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 6.25 nmol/L | Geometric Coefficient of Variation 23.1 |
| E10+L5+M1000 Fed (R3) | Maximum Measured Concentration of Linagliptin in Plasma (Cmax) | 6.15 nmol/L | Geometric Coefficient of Variation 22.8 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [89.94, 105.71]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [103.41, 133.07]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [98.56, 107.1]
Primary
Maximum Measured Concentration of Metformin in Plasma (Cmax)
Maximum measured concentration of Metformin in plasma (Cmax) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Maximum Measured Concentration of Metformin in Plasma (Cmax) | 1290 ng/mL | Geometric Coefficient of Variation 25 |
| E25+L5+M1000 Fed (R1) | Maximum Measured Concentration of Metformin in Plasma (Cmax) | 1300 ng/mL | Geometric Coefficient of Variation 21.4 |
| FDC 25 Fast (T2) | Maximum Measured Concentration of Metformin in Plasma (Cmax) | 1010 ng/mL | Geometric Coefficient of Variation 31.1 |
| E25+L5+M1000 Fast (R2) | Maximum Measured Concentration of Metformin in Plasma (Cmax) | 1020 ng/mL | Geometric Coefficient of Variation 32.8 |
| FDC 10 Fed (T3) | Maximum Measured Concentration of Metformin in Plasma (Cmax) | 1170 ng/mL | Geometric Coefficient of Variation 33.3 |
| E10+L5+M1000 Fed (R3) | Maximum Measured Concentration of Metformin in Plasma (Cmax) | 1150 ng/mL | Geometric Coefficient of Variation 32.6 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [91.46, 104.94]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [90.23, 110.91]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [94.58, 108.38]
Secondary
Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of the Empagliflozin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 6060 nmol*h/L | Geometric Coefficient of Variation 25.7 |
| E25+L5+M1000 Fed (R1) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 6190 nmol*h/L | Geometric Coefficient of Variation 22.5 |
| FDC 25 Fast (T2) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 6490 nmol*h/L | Geometric Coefficient of Variation 20 |
| E25+L5+M1000 Fast (R2) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 6300 nmol*h/L | Geometric Coefficient of Variation 18.7 |
| FDC 10 Fed (T3) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2130 nmol*h/L | Geometric Coefficient of Variation 15.5 |
| E10+L5+M1000 Fed (R3) | Area Under the Concentration-time Curve of the Empagliflozin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2180 nmol*h/L | Geometric Coefficient of Variation 15.4 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [92.86, 100.54]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [97.96, 103.86]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [95.81, 103.86]
Secondary
Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of the Linagliptin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 465 nmol*h/L | Geometric Coefficient of Variation 27.2 |
| E25+L5+M1000 Fed (R1) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 483 nmol*h/L | Geometric Coefficient of Variation 24.8 |
| FDC 25 Fast (T2) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 477 nmol*h/L | Geometric Coefficient of Variation 31.1 |
| E25+L5+M1000 Fast (R2) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 443 nmol*h/L | Geometric Coefficient of Variation 25.2 |
| FDC 10 Fed (T3) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 424 nmol*h/L | Geometric Coefficient of Variation 27.6 |
| E10+L5+M1000 Fed (R3) | Area Under the Concentration-time Curve of the Linagliptin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 420 nmol*h/L | Geometric Coefficient of Variation 27.1 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [87.36, 103.48]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [98.78, 113.15]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [92, 112.22]
Secondary
Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of the Metformin in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is presented
Time frame: 1.5 hours (h) before drug administration and 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 7h, 8h,10h, 12h, 24h, 34h, 48h, and 72h after drug administration
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| FDC 25 Fed (T1) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 14100 ng*h/mL | Geometric Coefficient of Variation 29.3 |
| E25+L5+M1000 Fed (R1) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 14100 ng*h/mL | Geometric Coefficient of Variation 30 |
| FDC 25 Fast (T2) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 8260 ng*h/mL | Geometric Coefficient of Variation 29.2 |
| E25+L5+M1000 Fast (R2) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 8600 ng*h/mL | Geometric Coefficient of Variation 33.2 |
| FDC 10 Fed (T3) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 12200 ng*h/mL | Geometric Coefficient of Variation 25.8 |
| E10+L5+M1000 Fed (R3) | Area Under the Concentration-time Curve of the Metformin in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 12400 ng*h/mL | Geometric Coefficient of Variation 25 |
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [90.94, 102.56]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [87.5, 104.01]
Comparison: The statistical model used was an Analysis of variance (ANOVA) model on the logarithmic scale. 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.90% CI: [92.44, 104.85]