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.

Study Overview

• Status: Completed
• Conditions: Pain Disorders
• Intervention / Treatment: Drug: KSL 40 mg; Drug: OKi® 80 mg

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).

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• Switzerland
  • Arzo, Switzerland, CH-6864
    • CROSS Research S.A., Phase I Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Test - Reference (KSL 40 mg - OKi® 80 mg); In this arm, a single dose of the test product (1 tablet; 40 mg KLS) was orally administered, under fasting conditions, in the first study period (day 1, 08:00±1h), and, after a wash-out period of at least 4 days, a single dose of the reference product OKi® 80 mg (half a sachet, 40 mg KLS) was orally administered, under fasting conditions, in the second study period (day 1, Visit 5, 08:00 ±1h).	Drug: KSL 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).; Other Names: Ketoprofen lysine salt; Drug: OKi® 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).; Other Names: Ketoprofen lysine salt
Experimental: Reference - Test (OKi® 80 mg - KSL 40 mg); In this arm, a single dose of the reference product OKi® 80 mg (half a sachet, 40 mg KLS) was orally administered, under fasting conditions, in the first study period (day 1, Visit 3, 08:00 ±1h) and, after a wash-out period of at least 4 days, a single dose of the test product (1 tablet; 40 mg KLS) was orally administered, under fasting conditions, in the second study period (day 1, Visit 5, 08:00±1h).	Drug: KSL 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).; Other Names: Ketoprofen lysine salt; Drug: OKi® 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).; Other Names: Ketoprofen lysine salt

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose
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.	pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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: 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.	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: 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.	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: Frel	Frel = Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference)	0, 1, 2, 3, 4, 5, 6, 7 and 8 hours post-dose
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.	From Day -14 to Day 1 of period 2 (Final visit/ETV), approximately 1 month

Collaborators and Investigators

• Sponsor: Dompé Farmaceutici S.p.A
• Collaborators: Cross Research S.A.
• Investigators: Principal Investigator: Milko Radicioni, MD, CROSS Research S.A., Phase I Unit

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2014
• Primary Completion (Actual): December 16, 2014
• Study Completion (Actual): April 22, 2015

Study Registration Dates

• First Submitted: December 15, 2014
• First Submitted That Met QC Criteria: January 28, 2015
• First Posted (Estimated): January 29, 2015

Study Record Updates

• Last Update Posted (Actual): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: neuralgia; headache; dental pain; dysmenorrhoea; muscular and osteoarticular pain
• Additional Relevant MeSH Terms: Mental Disorders; Somatoform Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Ketoprofen; Ketoprofen lysine
• Other Study ID Numbers: KSL0114

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No