Study to Investigate the Relative Bioavailability of Ibuprofen in Healthy Volunteers

Study Overview
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Brief Summary
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Study to demonstrate average bioequivalence between a 400 mg ibuprofen extrudate tablet (Test) and a 400 mg ibuprofen lysinate tablet (Dolormin extra ®; reference 1) under fasted conditions. Study to determine the relative bioavailability of ibuprofen following single administration of a 400 mg ibuprofen extrudate tablet (Test) compared to a 400 mg ibuprofen tablet (Brufen® 400mg, Denmark; Reference 2) under fasted conditions. Study to determine the relative bioavailability of ibuprofen following single administration of a 400 mg ibuprofen extrudate tablet (Test) compared to a 400 mg ibuprofen lysinate tablet (Dolormin extra ®; reference 1) or a 400 mg ibuprofen tablet (Brufen® 400mg, Denmark; Reference 2), respectively, under fed conditions. Study to evaluate the effect of food on the pharmacokinetics of ibuprofen for all three formulations.

Official Title
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Open-label, Randomised, Single Dose, Four-way Crossover Study to Investigate the Relative Bioavailability of a 400 mg Ibuprofen Extrudate Tablet Compared to a 400 mg Ibuprofen Lysinate Tablet (Dolormin Extra®) and a 400 mg Ibuprofen Tablet (Brufen® 400 mg, Denmark) in Fasted Condition and After Ingestion of a Standardised Meal in Healthy Male and Female Volunteers.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Ibuprofen extrudate
* Drug: Ibuprofen lysinate
* Drug: Ibuprofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, clinical laboratory tests: No finding deviating from normal and of clinical relevance No evidence of a clinically relevant concomitant disease. Age ≥ 21 and Age ≤ 50 years BMI ≥ 18.5 and BMI ≤ 29.9 kg/m2 (Body Mass Index) Signed and dated written informed consent prior to admission to the study in accordance with GCP (Good Clinical Practice) and the local legislation Exclusion Criteria: Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of gastrointestinal tract (except appendectomy) History of recent surgery including dental surgery History of gastrointestinal ulcer or gastrointestinal inflammation (gastritis, ulcerative colitis, Crohn's disease) Blood dyscrasias of unknown origin Subjects with porphyries diseases Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders History of relevant orthostatic hypotension, fainting spells or blackouts Chronic or relevant acute infections History of allergy/hypersensitivity/allergic rhinitis (including drug allergy) which is deemed relevant to he trial as judged by the investigator Intake of drugs with a long half-life (> 24 hours) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial except substitution therapy (thyroid, ovaries) and hormonal contraception Use of any drugs, which might influence the results of the trial (within 10 days prior to administration or during the trial) Participation in another trial with an investigational drug (within two months prior to administration or during the trial) Smoker (more than 10 cigarettes or 3 cigars or 3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 60 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) Excessive physical activities (within one week prior to administration or during the trial) Any laboratory value outside the reference range of clinical relevance Inability to comply with dietary regimen of study centre For female subjects: Pregnancy Positive pregnancy test No adequate contraception e.g. oral contraceptives, sterilisation, IUP (intrauterine pessary: in case a IUP was used for contraception, volunteers must be advised to employ additional contraceptive measures (e.g. condom by partner) because prostaglandin inhibition may alter IUP contraceptive efficacy) Inability to maintain this adequate contraception during the whole study period Lactation period

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Ibuprofen extrudate, fed state<br> | Drug: Ibuprofen extrudate<br> <br> |
| Experimental: B: Ibuprofen extrudate, fasted state<br> | Drug: Ibuprofen extrudate<br> <br> |
| Active Comparator: C: Ibuprofen lysinate tablet, fed state<br> | Drug: Ibuprofen lysinate<br> <br> |
| Active Comparator: D: Ibuprofen lysinate tablet, fasted state<br> | Drug: Ibuprofen lysinate<br> <br> |
| Active Comparator: E: Ibuprofen tablet, fed state<br> | Drug: Ibuprofen<br> <br> |
| Active Comparator: F: Ibuprofen tablet, fasted state<br> | Drug: Ibuprofen<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-∞ (area under the concentration-time curve of the analyte in plasma from zero time to infinity) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| Cmax (maximum observed concentration of the analyte in plasma) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| AUC0-tz (area under the concentration-time curve of the analyte in plasma from zero time to the time of the last quantifiable drug concentration) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Individual time courses of the ibuprofen plasma concentrations |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| AUCtrunc (Area under the concentration-time curve of the analyte in plasma from zero time to median tmax values of the reference formulation) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| tmax (time to reach Cmax) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| t1/2 (terminal half-life of the analyte in plasma) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| λz (terminal rate constant of the analyte in plasma) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| MRTtot (total mean residence time of the analyte molecules in the body) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| CL/F (total clearance of the analyte in plasma following extravascular administration) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| Vz/F (apparent volume of distribution during the terminal phase λz following extravascular administration) |  | Pre-dose and 15, 30, 45 min, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24 hours after treatment on day 1 of visits 2-5 | 
| Number of patients with adverse events |  | up to 24 days | 
| Number of patients with abnormal changes in laboratory parameters |  | up to 8 days following last drug administration | 
| Number of patients with clinically significant changes in vital signs (blood pressure (BP), pulse rate (PR)) |  | up to 8 days following last drug administration | 
| Number of patients with abnormal changes in 12-lead electrocardiogram (ECG) |  | up to 8 days following last drug administration | 
| Number of patients with abnormal findings in physical examination |  | up to 8 days following last drug administration | 
| Assessment of tolerability on a 4-point scale |  | up to 8 days following last drug administration |