Healthy
Conditions
Brief summary
The objective of the trial is to compare to combination of 400 mg ibuprofen and 100 mg caffeine against 400 mg ibuprofen alone under fed conditions
Interventions
DRUGIbuprofen
DRUGCaffeine
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy males and females, 18 to 50 years (inclusive) at time of screening. * Body Mass Index (BMI) between 18.5 and 29.9 kg/m2 (inclusive). * Body mass not less than 50 kg. * Medical history, vital signs, physical examination, standard 12-lead electrocardiogram (ECG) and laboratory investigations must be clinically acceptable or within laboratory reference ranges for the relevant laboratory tests, unless the PI considers the deviation to be irrelevant for the purpose of the study. * Non-smokers and mild or moderate smokers (\<= 10 cigarettes or pipes per day). Further inclusion criteria apply
Exclusion criteria
* Evidence of psychiatric disorder, antagonistic personality, poor motivation, emotional or intellectual problems likely to limit the validity of consent to participate in the study or limit the ability to comply with protocol requirements. * Current alcohol use \> 21 units of alcohol per week for males and \> 14 units of alcohol per week for females. One unit is equal to beer \[200 mL/10 ounces\], wine \[100 mL/4 ounces\], or distilled spirits \[25 mL/1 ounce\]) per day * Regular exposure to substances of abuse (other than alcohol) within the past year. * Use of any medication, prescribed or over-the-counter or herbal remedies, within 2 weeks before the first administration of IMP except if this will not affect the outcome of the study in the opinion of the PI. In this study the concomitant use of hormonal contraceptives is allowed. * Participation in another study with an experimental drug, where the last administration of the previous IMP was within 8 weeks (or within 5 elimination half-lives for chemical entities or 2 elimination half-lives for anti-bodies or insulin), whichever is the longer) before administration of IMP in this study, at the discretion of the PI. * Treatment within the previous 3 months before the first administration of IMP with any drug with a well-defined potential for adversely affecting a major organ or system. * History of hypersensitivity or allergy (angioedema or urticaria) to the IMP or its excipients or any related medication (Aspirin or any other NSAID). * Diagnosis of hypotension made during the screening period. * Diagnosis of hypertension made during the screening period or current diagnosis of hypertension. * Resting pulse of \> 100 beats per minute or \< 40 beats per minute during the screening period, either supine or standing. * Renal impairment. * Positive urine screen for drugs of abuse. In case of a positive result the urine screen for drugs of abuse may be repeated once at the discretion of the PI. Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-t of Ibuprofen | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the area under the plasma concentration of ibuprofen versus time curve, from time zero to t, where t is the time of the last quantifiable concentration (AUC0-t). |
| Cmax of Ibuprofen | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the Cmax of ibuprofen in plasma obtained directly from the concentration-time data. |
| Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, From Time Zero to t (AUC0-t) | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the area under the plasma concentration of S-ibuprofen versus time curve, from time zero to t, where t is the time of the last quantifiable concentration (AUC0-t). |
| AUC0-t of R-ibuprofen | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the area under the plasma concentration of R-ibuprofen versus time curve, from time zero to t, where t is the time of the last quantifiable concentration (AUC0-t). |
| Maximum Observed Plasma Concentration (Cmax) of S-ibuprofen | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the maximum observed concentration (Cmax) of S-ibuprofen in plasma obtained directly from the concentration-time data. |
| Cmax of R-ibuprofen | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the Cmax of R-ibuprofen in plasma obtained directly from the concentration-time data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-INF of R-ibuprofen | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the area under the plasma concentration of R-ibuprofen versus time curve, with extrapolation to infinity (AUC0-INF). |
| AUC0-INF of Ibuprofen | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the area under the plasma concentration of ibuprofen versus time curve, with extrapolation to infinity (AUC0-INF). |
| Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, With Extrapolation to Infinity (AUC0-INF) | Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose | This outcome measure presents the area under the plasma concentration of S-ibuprofen versus time curve, with extrapolation to infinity (AUC0-INF). |
Countries
South Africa
Participant flow
Pre-assignment details
All subjects were screened for eligibility to participate in the trial. Subjects attended a specialist site ensured that they (the subjects) met all inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Ref - Test Subjects received the reference product (Ref) which was a single oral dose (1 film-coated tablet) of 400 milligram (mg) ibuprofen (equivalent to 684 mg ibuprofen lysinate, trade name: Dolormin® Extra) under fed conditions. After a washout period of at least 6 calendar days, the subjects received the test product (Test), which was a single oral dose of 400 mg ibuprofen acid and 100 mg caffeine in a film coated tablet as a fixed dose combination (FDC), under fed conditions. Finally the subjects had a follow-up phase of 72 hours. | 18 |
| Test - Ref Subjects received the test product (Test) which was a single oral dose of 400 mg ibuprofen acid and 100 mg caffeine in a film coated tablet as a FDC under fed conditions. After a washout period of at least 6 calendar days, the subjects received the reference product (Ref), which was a single oral dose (1 film-coated tablet) of 400 milligram (mg) ibuprofen (equivalent to 684 mg ibuprofen lysinate, trade name: Dolormin® Extra), under fed conditions. Finally the subjects had a follow-up phase of 72 hours. | 18 |
| Total | 36 |
Baseline characteristics
| Characteristic | Ref - Test | Test - Ref | Total |
|---|---|---|---|
| Age, Continuous | 29.8 years STANDARD_DEVIATION 8.49 | 26.1 years STANDARD_DEVIATION 5.59 | 28.0 years STANDARD_DEVIATION 7.33 |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Male | 12 Participants | 13 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 36 | 0 / 36 |
| serious Total, serious adverse events | 0 / 36 | 0 / 36 |
Outcome results
Primary
Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, From Time Zero to t (AUC0-t)
This outcome measure presents the area under the plasma concentration of S-ibuprofen versus time curve, from time zero to t, where t is the time of the last quantifiable concentration (AUC0-t).
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, From Time Zero to t (AUC0-t) | 65110 hour (h)*ng/mL | Geometric Coefficient of Variation 21.9 |
| Test Product | Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, From Time Zero to t (AUC0-t) | 63150 hour (h)*ng/mL | Geometric Coefficient of Variation 21.7 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [94.61, 100.19]ANOVA
Primary
AUC0-t of Ibuprofen
This outcome measure presents the area under the plasma concentration of ibuprofen versus time curve, from time zero to t, where t is the time of the last quantifiable concentration (AUC0-t).
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | AUC0-t of Ibuprofen | 108400 h*ng/mL | Geometric Coefficient of Variation 18.4 |
| Test Product | AUC0-t of Ibuprofen | 105300 h*ng/mL | Geometric Coefficient of Variation 16.9 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [94.5, 100.73]ANOVA
Primary
AUC0-t of R-ibuprofen
This outcome measure presents the area under the plasma concentration of R-ibuprofen versus time curve, from time zero to t, where t is the time of the last quantifiable concentration (AUC0-t).
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | AUC0-t of R-ibuprofen | 42480 h*ng/mL | Geometric Coefficient of Variation 19 |
| Test Product | AUC0-t of R-ibuprofen | 41200 h*ng/mL | Geometric Coefficient of Variation 15.9 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [92.57, 102.8]ANOVA
Primary
Cmax of Ibuprofen
This outcome measure presents the Cmax of ibuprofen in plasma obtained directly from the concentration-time data.
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | Cmax of Ibuprofen | 23557.9 ng/mL | Geometric Coefficient of Variation 34.8 |
| Test Product | Cmax of Ibuprofen | 26309.5 ng/mL | Geometric Coefficient of Variation 30.3 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [98.49, 128.94]ANOVA
Primary
Cmax of R-ibuprofen
This outcome measure presents the Cmax of R-ibuprofen in plasma obtained directly from the concentration-time data.
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | Cmax of R-ibuprofen | 10495.7 ng/mL | Geometric Coefficient of Variation 32.7 |
| Test Product | Cmax of R-ibuprofen | 11454.6 ng/mL | Geometric Coefficient of Variation 26.6 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [96.32, 125.97]ANOVA
Primary
Maximum Observed Plasma Concentration (Cmax) of S-ibuprofen
This outcome measure presents the maximum observed concentration (Cmax) of S-ibuprofen in plasma obtained directly from the concentration-time data.
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: Pharmacokinetic (PK) population: all subjects who completed the PK sampling in both periods and with no major protocol deviations considered to impact on the analysis of the PK data were included.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | Maximum Observed Plasma Concentration (Cmax) of S-ibuprofen | 13268.7 nanogram (ng)/ millilitre (mL) | Geometric Coefficient of Variation 38 |
| Test Product | Maximum Observed Plasma Concentration (Cmax) of S-ibuprofen | 14967.2 nanogram (ng)/ millilitre (mL) | Geometric Coefficient of Variation 34.9 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% confidence interval (CI) was provided.90% CI: [98.99, 130.75]ANOVA
Secondary
Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, With Extrapolation to Infinity (AUC0-INF)
This outcome measure presents the area under the plasma concentration of S-ibuprofen versus time curve, with extrapolation to infinity (AUC0-INF).
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, With Extrapolation to Infinity (AUC0-INF) | 68900 h*ng/mL | Geometric Coefficient of Variation 17.2 |
| Test Product | Area Under the Plasma Concentration of S-ibuprofen Versus Time Curve, With Extrapolation to Infinity (AUC0-INF) | 64990 h*ng/mL | Geometric Coefficient of Variation 20.6 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [93.74, 99.28]ANOVA
Secondary
AUC0-INF of Ibuprofen
This outcome measure presents the area under the plasma concentration of ibuprofen versus time curve, with extrapolation to infinity (AUC0-INF).
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | AUC0-INF of Ibuprofen | 113200 h*ng/mL | Geometric Coefficient of Variation 14.6 |
| Test Product | AUC0-INF of Ibuprofen | 107300 h*ng/mL | Geometric Coefficient of Variation 16.4 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [93.75, 100.01]ANOVA
Secondary
AUC0-INF of R-ibuprofen
This outcome measure presents the area under the plasma concentration of R-ibuprofen versus time curve, with extrapolation to infinity (AUC0-INF).
Time frame: Within 2 hours prior to dosing and at 5, 10,15, 30 and 45 minutes and 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours post-dose
Population: PK population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Reference Product | AUC0-INF of R-ibuprofen | 43910 h*ng/mL | Geometric Coefficient of Variation 17.2 |
| Test Product | AUC0-INF of R-ibuprofen | 41960 h*ng/mL | Geometric Coefficient of Variation 16.3 |
Comparison: Relative bioavailability \[%\] was estimated by the ratios of the geometric means (100\*test/reference \[T/R\]). Additionally, it's two-sided 90% CI was provided.90% CI: [92.22, 102.46]ANOVA