Pain Disorders
Conditions
Keywords
headache, dental pain, neuralgia, dysmenorrhoea, muscular and osteoarticular pain
Brief summary
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.
Detailed description
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).
Interventions
DRUGKSL 40 mg
Ketoprofen lysine salt (KLS) immediate release oral tablets 40 mg, corresponding to 25 mg of ketoprofen free acid. Ketoprofen lysine salt was administered according to the randomisation list and the cross-over design. One (1) tablet of test formulation was administered to the subjects in the morning with 240 mL of still mineral water. Afterwards, no fluid intake was permitted for 2 h. All subjects were under fasting conditions from the evening before investigational product administration (i.e. for at least 10 h, overnight).
DRUGOKi® 80 mg
OKi® 80 mg granules for oral solution (bipartite sachets: each half sachet containing 40 mg of KLS corresponding to 25 mg of ketoprofen free acid). Ketoprofen lysine salt was administered according to the randomisation list and the cross-over design. The content of half sachet of the reference formulation was dissolved in 190 mL of still mineral water. The subject drank the entire solution immediately. Then the glass was rinsed with 50 mL of still mineral water and the subject drank the rinse immediately. Afterwards, no fluid intake was permitted for 2 h. All subjects were under fasting conditions from the evening before investigational product administration (i.e. for at least 10 h, overnight).
Sponsors
Cross Research S.A.
Dompé Farmaceutici S.p.A
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ketoprofen Plasma PK Parameters: Cmax | 0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose | Cmax = maximum plasma concentration. Cmax a of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder. |
| Ketoprofen Plasma PK Parameters: AUC0-t | pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose. | AUC0-t = Area under the concentration-time curve from administration to the last observed concentration time t, calculated with the linear trapezoidal method. AUC0-t of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder specified. Please note that AUC0-t was considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0-∞ equalled or exceeded a factor of 0.8, i.e. if %AUCextra was \< 20%. Arithmetic means + standard deviation are reported hereunder. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ketoprofen Plasma PK Parameters: T1/2 | pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose. | T1/2 = Half-life, calculated, if feasible, as ln2/λz. T1/2 (0-8 hours) of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose. |
| Ketoprofen Plasma PK Parameters: AUC0-∞ | pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose | AUC0-∞ = Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. AUC0-∞ of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder. |
| Number of TEAEs | From Day -14 to Day 1 of period 2 (Final visit/ETV), approximately 1 month | TEAE = Treatment Emergent Adverse Events. TEAEs were assessed throughout the study, from informed consent up to the final visit / early termination visit (ETV), which takes place after visit 5 on day 1 of period 2, more precisely after the 8 h blood sampling and vital signs check. |
| Ketoprofen Plasma PK Parameters: Frel | 0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose | Frel = Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference) |
| Ketoprofen Plasma PK Parameters: Tmax | pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose. | Tmax = Time to achieve Cmax. Tmax (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose. |
Countries
Switzerland
Participant flow
Recruitment details
30 healthy volunteers were randomized, receiving a single dose of Test and Reference treatment. Based on the cross-over design, a single dose of product was given orally in one of the two possible sequences: in the test-reference arm, subjects received Ketoprofen lysine salt (KLS) firstly and then the reference product OKI. In the Reference-Test arm, subjects received reference product OKi first, then Ketoprofen lysine salt (KLS)). A wash-out interval separated the 2 treatment periods.
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Enrolled Set: all enrolled subjects. This analysis set was used for the analysis of demographic, baseline and background characteristics.
Safety Set: all subjects who received at least one dose of investigational medicinal product. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Age, Continuous | 38.7 years STANDARD_DEVIATION 8.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment Switzerland | 30 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 0 / 30 |
| other Total, other adverse events | 1 / 30 | 2 / 30 |
| serious Total, serious adverse events | 0 / 30 | 0 / 30 |
Outcome results
Primary
Ketoprofen Plasma PK Parameters: AUC0-t
AUC0-t = Area under the concentration-time curve from administration to the last observed concentration time t, calculated with the linear trapezoidal method. AUC0-t of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder specified. Please note that AUC0-t was considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0-∞ equalled or exceeded a factor of 0.8, i.e. if %AUCextra was \< 20%. Arithmetic means + standard deviation are reported hereunder.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and have evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSL 40 mg (Test Product) | Ketoprofen Plasma PK Parameters: AUC0-t | 4.53 h*μg/mL | Standard Deviation 1.35 |
| OKi® 80 mg (Reference Product) | Ketoprofen Plasma PK Parameters: AUC0-t | 4.12 h*μg/mL | Standard Deviation 1.35 |
p-value: 0.002394.12% CI: [104.26, 117.38]ANOVA
Primary
Ketoprofen Plasma PK Parameters: Cmax
Cmax = maximum plasma concentration. Cmax a of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder.
Time frame: 0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and have evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSL 40 mg (Test Product) | Ketoprofen Plasma PK Parameters: Cmax | 3.61 μg/mL | Standard Deviation 1.17 |
| OKi® 80 mg (Reference Product) | Ketoprofen Plasma PK Parameters: Cmax | 3.40 μg/mL | Standard Deviation 1.38 |
p-value: 0.145594.12% CI: [97.57, 119.81]ANOVA
Secondary
Ketoprofen Plasma PK Parameters: AUC0-∞
AUC0-∞ = Area under the concentration-time curve extrapolated to infinity, calculated, if feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration. AUC0-∞ of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference products. Plasma concentrations of ketoprofen were measured in each study period at the timepoints hereunder reported. Arithmetic means + standard deviation are reported hereunder.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and have evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSL 40 mg (Test Product) | Ketoprofen Plasma PK Parameters: AUC0-∞ | 4.64 h*μg/mL | Standard Deviation 1.4 |
| OKi® 80 mg (Reference Product) | Ketoprofen Plasma PK Parameters: AUC0-∞ | 4.22 h*μg/mL | Standard Deviation 1.39 |
p-value: 0.002194.12% CI: [104.35, 117.41]ANOVA
Secondary
Ketoprofen Plasma PK Parameters: Frel
Frel = Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)
Time frame: 0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and have evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSL 40 mg (Test Product) | Ketoprofen Plasma PK Parameters: Frel | 112.07 % of bioavailability | Standard Deviation 18.7 |
Secondary
Ketoprofen Plasma PK Parameters: T1/2
T1/2 = Half-life, calculated, if feasible, as ln2/λz. T1/2 (0-8 hours) of ketoprofen was calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and have evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSL 40 mg (Test Product) | Ketoprofen Plasma PK Parameters: T1/2 | 1.64 h | Standard Deviation 0.17 |
| OKi® 80 mg (Reference Product) | Ketoprofen Plasma PK Parameters: T1/2 | 1.64 h | Standard Deviation 0.17 |
Secondary
Ketoprofen Plasma PK Parameters: Tmax
Tmax = Time to achieve Cmax. Tmax (0-8 hours) of ketoprofen calculated from plasma concentrations after single oral dose of test and reference. Plasma concentrations of ketoprofen were measured in each study period at the following timepoints: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Time frame: pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.
Population: PK set: all randomised subjects who fulfilled the study protocol requirements in terms of investigational medicinal products intake and have evaluable PK data readouts for the planned treatment comparisons, with no major deviations that could affect the PK results.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| KSL 40 mg (Test Product) | Ketoprofen Plasma PK Parameters: Tmax | 0.39 h | Standard Deviation 0.19 |
| OKi® 80 mg (Reference Product) | Ketoprofen Plasma PK Parameters: Tmax | 0.30 h | Standard Deviation 0.1 |
p-value: 0.0201Friedman
Secondary
Number of TEAEs
TEAE = Treatment Emergent Adverse Events. TEAEs were assessed throughout the study, from informed consent up to the final visit / early termination visit (ETV), which takes place after visit 5 on day 1 of period 2, more precisely after the 8 h blood sampling and vital signs check.
Time frame: From Day -14 to Day 1 of period 2 (Final visit/ETV), approximately 1 month
Population: Safety Set: all subjects who received at least one dose of investigational medicinal product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| KSL 40 mg (Test Product) | Number of TEAEs | serious TEAE | 0 number of events |
| KSL 40 mg (Test Product) | Number of TEAEs | TEAE related to treatment | 1 number of events |
| KSL 40 mg (Test Product) | Number of TEAEs | TEAE not related to treatment | 0 number of events |
| KSL 40 mg (Test Product) | Number of TEAEs | mild | 1 number of events |
| KSL 40 mg (Test Product) | Number of TEAEs | moderate | 0 number of events |
| KSL 40 mg (Test Product) | Number of TEAEs | severe | 0 number of events |
| KSL 40 mg (Test Product) | Number of TEAEs | TEAE leading to discontinuation | 0 number of events |
| OKi® 80 mg (Reference Product) | Number of TEAEs | serious TEAE | 0 number of events |
| OKi® 80 mg (Reference Product) | Number of TEAEs | moderate | 0 number of events |
| OKi® 80 mg (Reference Product) | Number of TEAEs | TEAE related to treatment | 2 number of events |
| OKi® 80 mg (Reference Product) | Number of TEAEs | TEAE leading to discontinuation | 0 number of events |
| OKi® 80 mg (Reference Product) | Number of TEAEs | TEAE not related to treatment | 0 number of events |
| OKi® 80 mg (Reference Product) | Number of TEAEs | severe | 0 number of events |
| OKi® 80 mg (Reference Product) | Number of TEAEs | mild | 2 number of events |