An Exploratory Pilot Study in Healthy Volunteers to Assess the Parameters for the Design of Bioequivalence Studies on Moderately Lipophilic, Moderately to Highly Protein Bound Drugs Using Dermal Open Flow Microperfusion (dOFM)

The overall aim of this clinical pilot study is to develop an optimal design (e.g. dose, study duration) for the main clinical study. In the main study factors that influence dOFM data variability will be measured to develop a general BE testing method using dOFM for dermatological drug products.

In this herein described pilot study 6 subjects will receive three different topical doses of Lidocaine 2.5% and Prilocaine 2.5% cream (2.5% lidocaine, 2.5% prilocaine, ACTAVIS LABORATORIES UT INC, US ) to select an optimal dose for the main study. Oraqix® gel (2.5% lidocaine, 2.5% prilocaine, Dentsply Pharmaceutical Inc., US) will be applied to assess whether it can be used as negative control in the main study. Blood samples will also be drawn at prior to dosing to establish a baseline, and at defined time points post-dose to assess systemic drug levels. Furthermore, lateral diffusion from a dosed site to an adjacent (non-dosed) test site will be evaluated in this pilot study. Different non-invasive devices will be tested to identify influencing factors for skin penetration in order to complete the available information on skin characteristics for the main study.

This pilot will be a single center, open label, exploratory research study to assess the dermal PK of marketed topical formulations of lidocaine/prilocaine in six healthy volunteers using dOFM. The study will be performed at the Clinical Research Center of the Medical University of Graz/Austria.The study comprises three visits, a screening visit (Visit 1), a study visit of approximately 28 h (Visit 2) for application of dermatological drug products, and an End-of-Study visit (Visit 3). In Visit 2 each subject will have nine test sites, four on the left thigh, four on the right thigh (resulting in 8 test sites on both thighs) and one on the arm. Each of the nine test site will have 2 dOFM probes resulting in 18 dOFM probes per subject. On six of the eight test sites on the thighs three different doses of Lidocaine 2.5% and Prilocaine 2.5% cream cream will be applied (5 mg/cm², 10 mg/cm² or 15 mg/cm²) to assess the dose for the main study. On another test site on the thighs Oraqix® gel will be applied to check if Oraqix® can be used as negative control in the main study. On the remaining test site on the thighs as well as on the test site on the arm no products will be applied to test for potential cross-talk between test sites by lateral diffusion and systemic redistribution, resulting in seven treated and two non-treated sites per subject. Additionally 8 blood samples will be drawn to rule out systemic appearance of lidocaine and/or prilocaine. Further, devices to identify possible factors influencing skin penetration will be measured on each thigh (e.g. TEWL).

Eligibility Criteria:
Inclusion Criteria:

Subject candidates must fulfill all of the following inclusion criteria to be eligible for participation in the study, unless otherwise specified:

1. 18 to 65 years inclusive,
2. Males and/or non-pregnant, non-breastfeeding females (subjects need to be informed about adequate contraceptive methods).
3. Able to read, understand, and sign the written informed consent form.
4. Willing to follow the protocol requirements and comply with protocol restrictions.

Exclusion Criteria:

Subject candidates must not be enrolled in the study if they meet any of the following criteria:

1. Social Habits

   1. Smoker who is not willing to restrain from smoking during the in-house-visit (Visit 2).
   2. History of drug and/or alcohol abuse within one year of start of study as judged by the investigator.
2. Medications

   a. Use of any medications (specially medication referred in the prescription information of the products) other than hormonal contraceptive or hormone replacement therapy within the 7 days or 5 half-life periods whichever is longer prior to the initial dose of study medication.
3. Diseases

   1. Congenital or idiopathic methemoglobinemia
   2. Glucose-6-phosphate dehydrogenase deficiencies
   3. Presence of any acute or chronic disease or malignancies unless deemed not clinically significant by the investigator.
4. Any reason which, in the opinion of the investigator, would prevent the subject from safely participating in the study.
5. Any abnormalities found at physical examination or vital signs, unless deemed not clinically significant by the investigator.
6. Clinically significant abnormal laboratory evaluation results, as deemed by the investigator.
7. Clinically significant abnormal 12-lead ECG at screening, as deemed by the investigator.
8. Positive results to the test for Hepatitis B antigen or Hepatitis C antibodies.
9. Positive HIV test.
10. Positive alcohol breath test.
11. Blood donation within 30 days or significant loss of blood or plasma (more than 550 ml) within 90 days prior to screening.
12. Subjects who have received an investigational drug within 30 days prior to the initial dose of study medication.
13. Any food allergy, intolerance, restriction or special diet that, in the opinion of the investigator, could contraindicate the subject's participation in this study.
14. Known or suspected allergy/hypersensitivity to lidocaine or prilocaine, known history of sensitivity to local anesthetics of the amide type or to any other component of the product, other related products, or any inactive ingredients.
15. Tattoos or broken and/or damaged skin at the application areas.
16. Active skin diseases like psoriasis or atopic dermatitis judged by the investigator.
17. Scarring at the anterior part of the thighs
18. Subjects prone to keloid or hypertrophic scar formation or any known wound healing disorder.
19. Recent and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.) judged by the investigator.
20. Not willing to avoid excessive sun exposure, steam baths, sauna, swimming and other strenuous activities between Visit 2 and the End-of-Study examination to ensure good tissue regeneration.
21. Not willing to refrain from shaving the anterior of the thighs or using skin care products on the anterior of the thighs for at least 5 days prior to start of Visit 2.
22. Pronounced hairiness on the thighs that may negatively affect BE testing.
23. Known allergy/hypersensitivity to any of the materials/supplies used during the study.
24. Presence of needle phobia.