S-flurbiprofen Bioavailability Trial to Compare a Newly Developed Patch vs. a Marketed Tablet

Characterisation of Relative Bioavailability of a Newly Developed S-flurbiprofen Containing Patch Formulation in Comparison With a Marketed Oral Flurbiprofen Containing Tablet Formulation - a Multiple Dose, Randomised, 2-period Crossover...

Teikoku Seiyaku Co., Ltd. (Japan) is developing a new Esflurbiprofen Hydrogel Patch (EFHP), a transdermal product containing 165 mg of the S-enantiomer of flurbiprofen (S-flurbiprofen) as its active pharmaceutical ingredient.

The present clinical trial will be conducted to characterise maximum observed systemic exposure of the newly developed EFHP (Test) vs. "Froben 100 mg" (Reference, containing 100 mg racemic flurbiprofen in a 1:1 ratio). Characterisation will be performed under steady state conditions in order to bridge the available safety information on the basis of the comparison of maximum observed systemic exposure by means of AUC0-24h,ss,P vs. AUC0-24,ss,T and Cmax,ss,P vs. Cmax,ss,T of S-flurbiprofen.

This single centre, open-label, randomised (order of treatments), balanced, multiple dose trial will be performed in a 2-period, 2-sequence-crossover design.

The Test Product (patch) will be applied once daily over 14 consecutive days, whereby each patch will remain applied for 24 h. Blood sampling will be performed after the 1st patch application over 24 h in order to characterise the single dose application and after the 14th patch application over 72 h in order to characterise pharmacokinetic parameters after multiple dosing including elimination phase. In between through values will be taken in the morning of specified study days to characterise steady-state built-up phase.

The Reference product will be administered after a light meal as single oral doses of 100 mg flurbiprofen three times daily (i.e. every 8 h) over 4 days. Blood sampling will be performed after the 10th tablet administration over 72 h in order to characterise pharmacokinetic parameters after multiple dosing including elimination phase. In between through values will be taken in the morning of study days 1 to 4 to characterise steady-state built-up phase.

The clinical trial will be performed as a cross-over investigation with intra-individual comparison, thus reducing variability of the pharmacokinetic parameters, which is supposed to be higher between subjects than within an individual subject.

Inclusion Criteria:

1. age: 18 to 64 years (inclusive)
2. body-mass index (BMI): >= 18.5 kg/m² and <= 30.0 kg/m²
3. good state of health
4. non-smoker or ex-smoker for at least 3 months
5. written informed consent, after having been informed about benefits and potential risks of the clinical trial, as well as details of the insurance taken out to cover the subjects participating in the clinical trial

Exclusion Criteria:

Safety concerns

1. existing cardiac and/or haematological diseases or pathological findings, which might interfere with the safety or tolerability of the active ingredient

2. existing or history of hypertension and/or heart failure

3. existing hepatic and/or renal diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient

4. existing gastrointestinal diseases or pathological findings, which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient

5. history of gastrointestinal bleeding or perforation related to previous NSAID therapy

6. active, or history of, ulcerative colitis, Crohn's disease, peptic ulceration or gastrointestinal haemorrhage

7. existing metabolic, endocrine and/or immunologic diseases or pathological findings, which might interfere with the safety or tolerability, and/or pharmacokinetics of the active ingredient

8. diabetes mellitus

9. hyperlipidaemia (LDL > 160 mg/dL; HDL < 35 mg/dL; triglycerides > 200 mg/dL; cholesterol > 240 mg/dL)

10. history of relevant CNS and/or psychiatric disorders and/or currently treated CNS and/or psychiatric disorders

11. presence or history of acute or chronic diseases of the skin (e.g. atopy, neurodermatitis, contact allergy, eczema, psoriasis, vitiligo, melanoma, squamous cell carcinoma), any dermatological condition or skin sensitivity which might interfere with the safety, tolerability, absorption and/or pharmacokinetics of the active ingredient

12. existing or history of bronchial asthma

13. known allergic reactions (e.g. bronchospasm, rhinitis, angioedema, or urticaria) to the active ingredients used, to acetylsalicylic acid or other NSAIDs, or to constituents of the pharmaceutical preparations

14. history of severe allergies or multiple drug allergies unless it is judged as not relevant for the clinical trial by the investigator

15. fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency

16. galactose intolerance or Lapp lactase deficiency

17. systolic blood pressure < 90 or > 139 mmHg

18. diastolic blood pressure < 60 or > 89 mmHg

19. heart rate < 50 bpm or > 90 bpm

20. QTc interval > 450 ms for men and > 470 ms for women

21. laboratory values out of normal range unless the deviation from normal is judged as not relevant for the clinical trial by the investigator

22. ASAT > 20% ULN, ALAT > 10% ULN, bilirubin > 20% ULN (except in case of existing Morbus Gilbert-Meulengracht deduced from anamnesis/medical history) and creatinine > 0.1 mg/dL ULN (limit of > 0.1 mg/dL correspondents to of > 9 µmol/l ULN).

23. positive anti-HIV-test (if positive to be verified by western blot), HBs-AG-test or anti-HCV-test

24. symptoms of, or diagnosis of COVID-19 within the last 14 days prior to individual enrolment of the subject

25. contact to persons in risk regions as defined by the Robert Koch Institute within the last 14 days prior to individual enrolment of the subject

26. direct contact to persons with symptoms of, or diagnosis of COVID-19 within the last 14 days prior to individual enrolment of the subject Lack of suitability for the clinical trial

27. skin abnormality (e.g. tattoo (including tattoo that was removed), scar, sunburn or obvious difference in skin colour), open sores, or excessive hair at the application site

28. acute or chronic diseases which may interfere with the pharmacokinetics of the IMP

29. history of or current drug or alcohol dependence

30. positive alcohol or drug test at screening examination

31. regular intake of alcoholic food or beverages of >= 24 g pure ethanol for male or >= 12 g pure ethanol for female per day

32. subjects who are on a diet which could affect the pharmacokinetics of the active ingredient

33. regular intake of caffeine containing food or beverages of >= 500 mg caffeine per day

34. blood donation or other blood loss of more than 400 ml within the last 2 months prior to individual enrolment of the subject

35. administration of any investigational medicinal product during the last 2 months prior to individual enrolment of the subject

36. regular treatment with any systemically available medication (except hormonal contraceptives and hormonal replacement therapy, e.g. estrogens, L-thyroxine)

37. subjects, who report a frequent occurrence of migraine attacks

    For female subjects with childbearing potential only:

38. positive pregnancy test at screening examination

39. pregnant or lactating women

40. female subjects who do not agree to apply highly effective contraceptive methods Administrative reasons

41. subjects suspected or known not to follow instructions

42. subjects who are unable to understand the written and verbal instructions, in particular regarding the risks and inconveniences they will be exposed to during their participation in the clinical trial