Ibuprofen Bioavailability Study

Study Overview
=================
Brief Summary
-----------------
This project is the in-house development of a 200 mg ibuprofen acid orodispersable tablet (ODT; meltlet). It is designed to appeal to consumers who want a dosage form that may be taken without water and can be used 'on the go'. Vanquish has an improved organoleptic profile compared to the currently marketed meltet by the Sponsor. ODTs are also considered as a suitable dosage form for children who may be reluctant to swallow tablets. This product has the potential for application in both adults and children due to the convenience of the format and the ease of administration for both groups. This will be the first pharmacokinetic (PK) assessment of the ibuprofen acid ODT formulation.

Official Title
-----------------
An Open Label, Randomised, Single Dose, Three-way Crossover Study to Compare the Bioavailability of 400 mg Ibuprofen From 2 x 200 mg Ibuprofen Acid Orodispersable Tablets, 2x 200 mg Ibuprofen Acid Tablets and 2 x 342 mg Ibuprofen Lysine Tablets in Fasted Healthy Volunteers

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Test - RB ibuprofen acid orodispersible tablets
* Drug: Reference - RB Nurofen ibuprofen acid tablets
* Drug: Comparator - Dolormin ibuprofen lysine tablets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects who have given written informed consent. Age: ≥ 18 years ≤ 50 years. Body Mass Index (BMI) of ≥ 18.0 and ≤ 30 kg/m2. Healthy as determined by past medical history, physical examination, vital signs, electrocardiogram (ECG), and laboratory tests at screening. Female subject of child bearing potential with a negative pregnancy test at the screening visit and willing to use an effective method of contraception unless of non-childbearing potential or where abstaining from sexual intercourse in line with the preferred and usual lifestyle of the subject from first dose until 3 months after the final dose of study medication. Female subject of non-child bearing potential with negative pregnancy test at the screening visit. Male subject willing to use an effective method of contraception unless anatomically sterile or where abstaining from sexual intercourse in line with the preferred and usual lifestyle of the subject from first dose until 3 months after the final dose of study medication. Exclusion Criteria: Pregnant or lactating females. A history and/or presence of significant disease of any body system, including significant psychiatric disorders, parasuicide. Any condition that may currently interfere with the absorption, distribution, metabolism or excretion of drugs. A history of allergy or intolerance related to treatment with ibuprofen, aspirin or other non-steriodal anti-inflammatory drugs (NSAIDs), or the excipients of the formulations A history of or active peptic or duodenal ulcers or gastrointestinal bleed or upper gastro-intestinal bleed, or other significant gastro-intestinal disorders. A history of frequent dyspepsia, e.g. heartburn or indigestion. A history of significant and frequent migraine. Current smokers or ex-smokers who have smoked or used nicotine replacement products during the 6 months prior to the first dose of study medication. A history of substance abuse (including alcohol). Consumption of foods or beverages containing caffeine (e.g. coffee, tea, cola and chocolate) above 300 mg caffeine per day, prior to 48 hours of each treatment period. (One cup of coffee equals approximately 50 mg caffeine). Those with positive test for drugs of abuse and alcohol. Ingestion of a prescribed drug at any time in the 14 days before the first dose of study medication (excluding hormonal contraceptives and hormone replacement therapy), or consumption of enzyme inhibitors or inducers 30 days prior to the first dose of study medication (such as barbiturates, carbamazepine, erythromycin, phenytoin, etc.). Ingestion of an over-the-counter preparation within 7 days before the first dose of study medication, including herbal medications, vitamins, fish oil supplements, ibuprofen and other NSAIDs. Those who have consumed grapefruit or grapefruit juice, pumelo or Seville oranges in the 7 days before the first dose of study medication. Donation of blood > 400 mL e.g. to the blood transfusion service in the 12 weeks prior to the first dose of study medication. Known human immune deficiency virus (HIV) positive status, or a positive viral serology test. Topical use of ibuprofen within 7 days before the first dose of study medication. Strenuous physical exercise from 48 hours prior to first dose of study medication. Those previously randomised into this study. Those who are an employee at the study site. Those who are a partner or first degree relative of the Investigator. Participation in a New Chemical Entity clinical study within the previous 3 months or a marketed drug clinical study within the 30 days before the first dose of study medication. Those unable in the opinion of the Investigator to comply fully with the study requirements.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Treatment Order: Test, Reference, Comparator | Drug: Test - RB ibuprofen acid orodispersible tablets<br>* RB ibuprofen acid orodispersible tablets, 2 x 200 mg, single dose, oral.<br>Drug: Reference - RB Nurofen ibuprofen acid tablets<br>* RB Nurofen ibuprofen acid tablets, 2 x 200 mg, single dose, oral.<br>Drug: Comparator - Dolormin ibuprofen lysine tablets<br>* Dolormin ibuprofen lysine tablets 2 x 342 mg (each 342 mg tablet contains 200 mg ibuprofen), single dose, oral.<br>|
| Experimental: 2<br>Treatment Order: Test, Comparator, Reference | Drug: Test - RB ibuprofen acid orodispersible tablets<br>* RB ibuprofen acid orodispersible tablets, 2 x 200 mg, single dose, oral.<br>Drug: Reference - RB Nurofen ibuprofen acid tablets<br>* RB Nurofen ibuprofen acid tablets, 2 x 200 mg, single dose, oral.<br>Drug: Comparator - Dolormin ibuprofen lysine tablets<br>* Dolormin ibuprofen lysine tablets 2 x 342 mg (each 342 mg tablet contains 200 mg ibuprofen), single dose, oral.<br>|
| Experimental: 3<br>Treatment Order: Reference, Test, Comparator | Drug: Test - RB ibuprofen acid orodispersible tablets<br>* RB ibuprofen acid orodispersible tablets, 2 x 200 mg, single dose, oral.<br>Drug: Reference - RB Nurofen ibuprofen acid tablets<br>* RB Nurofen ibuprofen acid tablets, 2 x 200 mg, single dose, oral.<br>Drug: Comparator - Dolormin ibuprofen lysine tablets<br>* Dolormin ibuprofen lysine tablets 2 x 342 mg (each 342 mg tablet contains 200 mg ibuprofen), single dose, oral.<br>|
| Experimental: 4<br>Treatment Order: Reference, Comparator, Test | Drug: Test - RB ibuprofen acid orodispersible tablets<br>* RB ibuprofen acid orodispersible tablets, 2 x 200 mg, single dose, oral.<br>Drug: Reference - RB Nurofen ibuprofen acid tablets<br>* RB Nurofen ibuprofen acid tablets, 2 x 200 mg, single dose, oral.<br>Drug: Comparator - Dolormin ibuprofen lysine tablets<br>* Dolormin ibuprofen lysine tablets 2 x 342 mg (each 342 mg tablet contains 200 mg ibuprofen), single dose, oral.<br>|
| Experimental: 5<br>Treatment Order: Comparator, Test, Reference | Drug: Test - RB ibuprofen acid orodispersible tablets<br>* RB ibuprofen acid orodispersible tablets, 2 x 200 mg, single dose, oral.<br>Drug: Reference - RB Nurofen ibuprofen acid tablets<br>* RB Nurofen ibuprofen acid tablets, 2 x 200 mg, single dose, oral.<br>Drug: Comparator - Dolormin ibuprofen lysine tablets<br>* Dolormin ibuprofen lysine tablets 2 x 342 mg (each 342 mg tablet contains 200 mg ibuprofen), single dose, oral.<br>|
| Experimental: 6<br>Treatment Order: Comparator, Reference, Test | Drug: Test - RB ibuprofen acid orodispersible tablets<br>* RB ibuprofen acid orodispersible tablets, 2 x 200 mg, single dose, oral.<br>Drug: Reference - RB Nurofen ibuprofen acid tablets<br>* RB Nurofen ibuprofen acid tablets, 2 x 200 mg, single dose, oral.<br>Drug: Comparator - Dolormin ibuprofen lysine tablets<br>* Dolormin ibuprofen lysine tablets 2 x 342 mg (each 342 mg tablet contains 200 mg ibuprofen), single dose, oral.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t - the area under plasma concentration curve from administration to last quantifiable concentration at time t. | The Test and Reference will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Reference ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%: | PK Analysis 0-12hrs | 
| Cmax - the maximum observed plasma concentration. | The Test and Reference will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Reference ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%: | PK Analysis 0-12hrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t - the area under plasma concentration curve from administration to last quantifiable concentration at time t. | The Test and Comparator will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%: | PK Analysis 0-12hrs | 
| Cmax - the maximum observed plasma concentration. | The Test and Comparator will be considered similar if for ibuprofen, for each corresponding PK parameter, the 90% confidence interval for the Test to Comparator ratio (rounded to two decimal places) of LS geometric means is fully contained within the interval 80.00 to 125.00%: | PK Analysis 0-12hrs | 
| Kel - Elimination rate constant | Secondary endpoint for Test, Reference and Comparator products | PK Analysis 0-12hrs | 
| AUC0-inf - Area under the plasma concentration-time curve from administration to infinity | Secondary endpoint for Test, Reference and Comparator products | PK Analysis 0-12hrs | 
| AUCR - Ratio AUC0-t/AUC0-inf | Secondary endpoint for Test, Reference and Comparator products | PK Analysis 0-12hrs | 
| Tmax - Time until Cmax is first achieved | Secondary endpoint for Test, Reference and Comparator products | PK Analysis 0-12hrs | 
| T1/2 - Plasma concentration (elimination) half-life | Secondary endpoint for Test, Reference and Comparator products | PK Analysis 0-12hrs | 
| Cn - The plasma concentration at each planned nominal time point. | Secondary endpoint for Test, Reference and Comparator products | PK Analysis 0-12hrs |