Crossover, Single Dose Randomized, Bioequivalence of Ketoprofen Lysine Salt Immediate Release vs Oral Solution

2-way Crossover, Single Dose Randomized Bioequivalence Phase I Study of Ketoprofen Lysine Salt as Immediate Release Tablets Formulation (40 mg) vs. Oral Solution (80 mg, Half Sachet) After Oral Administration to Healthy Volunteers.

Objectives:

The objective of the study was to investigate the bioequivalence between two formulations containing ketoprofen lysine salt (KLS) when administered as single oral doses in two consecutive study periods to healthy male and female volunteers under fasting conditions.

Primary end-point: to evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of ketoprofen after single dose administration of test and reference products.

Secondary end-points:

• to describe the pharmacokinetic (PK) profile of ketoprofen after single dose administration of test and reference products;
• to collect safety and tolerability data after single dose administration of test and reference products.

This was a single centre, single dose, open, randomised, two-way cross-over, two-stage bioequivalence study. According to the two-stage design of the study, an initial group of subjects was treated in study stage 1 and data were analysed. Since bioequivalence was demonstrated, according to the protocol the study was terminated after stage 1, and stage 2 was not performed.

The study was conducted as planned and consisted of a screening visit, a treatment phase of 2 study periods separated by a wash-out interval of at least 4 days and a final visit / early termination visit (ETV).

Considering the lack of information about the PK profile of the new formulation, it was decided to use a "two stage" bioequivalence study design, that allows a re-calculation of the sample size in case the number of subjects initially enrolled in the study is not large enough to provide a reliable answer to the questions addressed, due to a possible underestimation of the variability or misleading estimation of the point estimate for the test/reference ratio of the geometric means.

The sequence of treatments in the two study periods was assigned to each randomised subject according to a computer generated randomisation list.

A wash-out period of at least 4 days between the two administrations is justified by the elimination half-life of the ketoprofen (1-2 h).

Inclusion Criteria:

To be enrolled in this study, subjects must fulfil all these criteria:

1. Informed consent: signed written informed consent before inclusion in the study

2. Sex and Age: males/females, 18-55 years old inclusive

3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive

4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, pulse rate (PR) 50-90 bpm and body temperature (BT) ≤ 37.5° C, measured after 5 min of rest in the sitting position;

5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire study

6. Contraception and fertility (females only): females of child-bearing potential and with an active sexual life must be using at least one of the following reliable methods of contraception:

   • Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit
   • A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months before the screening visit
   • A male sexual partner who agrees to use a male condom with spermicide
   • A sterile sexual partner

Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be admitted. For all female subjects, pregnancy test result must be negative at screening.

Exclusion Criteria:

Subjects meeting any of these criteria will not be enrolled in the study:

1. Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (ketoprofen) and/or formulations' ingredients; history of hypersensitivity to drugs (in particular to NSAIDs) or allergic reactions in general, which the Investigator considers may affect the outcome of the study
5. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory (including asthma), skin, haematological, endocrine or neurological and autoimmune diseases that may interfere with the aim of the study
6. Medications: medications, including over the counter (OTC) drugs [in particular ketoprofen and acetylsalicylic acid (ASA) and NSAIDs in general], herbal remedies and food supplements taken 2 weeks before the start of the study. Hormonal contraceptives for females will be allowed
7. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study (date of the informed consent signature)
8. Blood donation: blood donations for 3 months before this study
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [> 1 drink/day for females and > 2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010 (6)], caffeine (> 5 cups coffee/tea/day) or tobacco abuse (≥ 6 cigarettes/day)
10. Drug test: positive result at the drug test at screening
11. Alcohol test: positive alcohol breath test at day -1
12. Diet: abnormal diets (< 1600 or > 3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians
13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating women