Relative Bioavailability of Empagliflozin/Metformin Fixed-dose Combination - Empagliflozin 12.5 mg + Metformin 850mg (Boehringer Ingelheim) Coated Tablet Versus Jardiance® 10mg (Reference 1: Boehringer Ingelheim) Coated Tablet and Glifage® 850mg (Reference 2: Merck S / A. ) Coated Tablet, Administered Together in Healthy Male and Female Subjects Under Fed Conditions: an Open-label, Randomised, Single-dose, Two-way Crossover Study
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 32
- 试验地点
- 1
- 主要终点
- 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)
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
盲法说明
The bioanalytical staff involved are blinded to treatment
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- 未提供
排除标准
- •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 exclusion criteria apply
研究组 & 干预措施
(A): empagliflozin 10mg (R1)+Glifage® 850mg (R2),then (B): FDC 12.5mg empagliflozin/850mg metformin
On Day 1 of Period 1 subjects 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 subjects 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.
干预措施: FDC 12.5mg empagliflozin/850mg metformin (Drug)
(A): empagliflozin 10mg (R1)+Glifage® 850mg (R2),then (B): FDC 12.5mg empagliflozin/850mg metformin
On Day 1 of Period 1 subjects 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 subjects 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.
干预措施: Empagliflozin (Drug)
(A): empagliflozin 10mg (R1)+Glifage® 850mg (R2),then (B): FDC 12.5mg empagliflozin/850mg metformin
On Day 1 of Period 1 subjects 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 subjects 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.
干预措施: Glifage® (Drug)
(B): FDC 12.5mg empagliflozin/850mg metformin,then (A): empagliflozin 10mg(R1) + Glifage® 850mg(R2)
On Day 1 of Period 1 subjects received treatment B: Fixed dose combination (FDC) tablet containing 12.5 milligram (mg) empagliflozin/850 mg metformin HCl, orally with 200 milliliter (mL) of water.
On Day 1 of Period 2 subjects received treatment A: Single dose tablet of 10mg empagliflozin and 850 mg of metformin hydrochloride (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.
干预措施: FDC 12.5mg empagliflozin/850mg metformin (Drug)
(B): FDC 12.5mg empagliflozin/850mg metformin,then (A): empagliflozin 10mg(R1) + Glifage® 850mg(R2)
On Day 1 of Period 1 subjects received treatment B: Fixed dose combination (FDC) tablet containing 12.5 milligram (mg) empagliflozin/850 mg metformin HCl, orally with 200 milliliter (mL) of water.
On Day 1 of Period 2 subjects received treatment A: Single dose tablet of 10mg empagliflozin and 850 mg of metformin hydrochloride (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.
干预措施: Empagliflozin (Drug)
(B): FDC 12.5mg empagliflozin/850mg metformin,then (A): empagliflozin 10mg(R1) + Glifage® 850mg(R2)
On Day 1 of Period 1 subjects received treatment B: Fixed dose combination (FDC) tablet containing 12.5 milligram (mg) empagliflozin/850 mg metformin HCl, orally with 200 milliliter (mL) of water.
On Day 1 of Period 2 subjects received treatment A: Single dose tablet of 10mg empagliflozin and 850 mg of metformin hydrochloride (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.
干预措施: Glifage® (Drug)
结局指标
主要结局
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)
时间窗: 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.
Area Under the Concentration-time Curve of Metformin in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
时间窗: 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.
Dose-normalized Maximum Measured Concentration of Empagliflozin (Cmax)
时间窗: 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.
Maximum Measured Concentration of Metformin (Cmax)
时间窗: 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.
次要结局
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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.)