An Exploratory Study in Healthy Volunteers to Identify Factors Influencing Bioequivalence Studies on Moderately Lipophilic Drugs Using Dermal Open Flow Microperfusion (dOFM)

Study Overview
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Brief Summary
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The overall aim of this clinical study is to develop a general bioequivalence (BE) testing method using dermal open flow microperfusion (dOFM) for dermatological drug products. In this study BE of different lidocaine/prilocaine products will be assessed and factors that influence dOFM data variability will be evaluated.

Detailed Description
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The study will involve 20 healthy adult participants. Dermal pharmacokinetic (PK) profile of three different lidocaine/prilocaine products will be assessed in parallel at different skin sites on the same participant. For BE evaluations a reference product will be compared against itself and an approved generic test product as positive control and against a non-equivalent test product as negative control. Additionally different non-invasive measurements (e.g. TEWL) will be conducted and results will be correlated with lidocaine/prilocaine PK data to identify factors that might influence skin penetration. dOFM probes will be inserted into the dermis to monitor the dermal drug concentrations up to 12 h post-dose in topically treated skin sites. Blood samples will be drawn to rule out systemic appearance of lidocaine and/or prilocaine.

Official Title
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An Exploratory Study in Healthy Volunteers to Identify Factors Influencing Bioequivalence Studies on Moderately Lipophilic Drugs Using Dermal Open Flow Microperfusion (dOFM)

Conditions
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Healthy, Dermal Pharmacokinetic Measurements

Intervention / Treatment
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* Drug: Lidocaine 2.5% and Prilocaine 2.5% cream, USP (Actavis Pharma incorporated, USA)
* Drug: Lidocaine 2.5% and Prilocaine 2.5% cream (E. Fougera & Co. a division of Fougera Pharmaceuticals Inc., USA)
* Drug: Oraqix Parodontal-Gel (Dentsply Detrey GmbH, Germany)
* Device: Dermal open flow microperfusion
* Procedure: Blood sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 to 65 years inclusive. Males and/or non-pregnant, non-breast feeding females (subjects need to be informed about adequate contraceptive methods). Able to read, understand, and sign the written informed consent form. Willing to follow the protocol requirements and comply with protocol restrictions. Exclusion Criteria: Social Habits Smoker who is not willing to restrain from smoking during the in-house visit (Visit 2). History of drug and/or alcohol abuse within one year of start of study as judged by the investigator. Medications: Current treatment with systemically effective corticosteroids, monoamine oxidase (MAO) inhibitors, systemic non-selective beta-blockers, warfarin or anticholinergic drugs, or use of any medications referred in the prescription information of the products. Hormonal contraceptive or hormone replacement therapy, routine vitamins or other prescribed medication are allowed if dose is stable. Diseases Congenital or idiopathic methemoglobinemia History of deep vein thrombosis (DVT)/pulmonary emboly (PE) Inherited blood disorders (such as factor V Leiden) who are prone to hypercoagulable state Glucose-6-phosphate dehydrogenase deficiencies Presence of any acute or chronic diseases or malignancies unless deemed not clinically significant by the investigator. Any reason which, in the opinion of the investigator, would prevent the subject from safely participating in the study. Any abnormalities found at physical examination or vital signs, unless deemed not clinically significant by the investigator. Clinically significant abnormal laboratory evaluation results, as deemed by the investigator. Clinically significant abnormal 12-lead ECG at screening, as deemed by the investigator. Positive results to the test for hepatitis B antigen or hepatitis C antibodies. Positive HIV test. Positive alcohol breath test. Blood donation within 30 days or significant loss of blood or plasma (more than 550 ml) within 90 days prior to screening. Subjects who have received an investigational drug within 30 days prior to the initial dose of study medication. Any food allergy, intolerance, restriction or special diet that, in the opinion of the investigator, could contraindicate the subject's participation in this study. 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. Tattoos or broken and/or damaged skin at the application areas. Active skin diseases like psoriasis or atopic dermatitis, as judged by the investigator. Scarring at the anterior part of the thighs. Subjects prone to keloid or hypertrophic scar formation or any known wound healing disorder. Recent and/or recurrent history of autonomic dysfunction (e.g., recurrent episodes of fainting, palpitations, etc.), as judged by the investigator. 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. 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. Pronounced hairiness on the thighs that may negatively affect BE testing. Known allergy/hypersensitivity to any of the materials/supplies used during the study. Presence of needle phobia.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dermal Pharmacokinetic study<br>Measurement of dermal pharmacokinetic (PK) parameter (AUC, Cmax) of lidocaine/ prilocaine using dOFM after topical application of three lidocaine/prilocaine products in 20 participants. After baseline sampling (1 hour pre-dose) the three lidocaine/prilocaine products will be applied and removed after 3 hours. ISF and blood sampling will be continued for a duration of 12 hours post-dose. Additionally different physical parameters (e.g. TEWL) will be measured. | Drug: Lidocaine 2.5% and Prilocaine 2.5% cream, USP (Actavis Pharma incorporated, USA)<br>* Topical application<br>* Other names: Reference product;Drug: Lidocaine 2.5% and Prilocaine 2.5% cream (E. Fougera & Co. a division of Fougera Pharmaceuticals Inc., USA)<br>* Topical application<br>* Other names: Generic test product;Drug: Oraqix Parodontal-Gel (Dentsply Detrey GmbH, Germany)<br>* Topical application<br>* Other names: Non-equivalent test product;Device: Dermal open flow microperfusion<br>* Dermal open flow microperfusion will be used to collect interstitial fluid in order to assess lidocaine/prilocaine concentration in the dermis. 16 dOFM probes will be implanted per participant (8 test-sites; 2 dOFM probes per test-site). From each dOFM probe 13 samples will be taken (1 pre-dose, 12 post-dose).<br>Procedure: Blood sampling<br>* 1 sample will be taken pre-dose and 12 samples post-dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the dermal concentration versus time curve for lidocaine | Dermal concentrations (ng/mL) of lidocaine will be measured to calculate the area under the dermal concentration versus time curve AUC (ng*h/mL). | 13 hours | 
| Area under the dermal concentration versus time curve for prilocaine | Dermal concentrations (ng/mL) of prilocaine will be measured to calculate the area under the dermal concentration versus time curve AUC (ng*h/mL). | 13 hours | 
| Maximal dermal concentration of lidocaine | Dermal concentrations (ng/mL) of lidocaine will be measured to calculate the maximal dermal concentration (ng/mL). | 13 hours | 
| Maximal dermal concentration of prilocaine | Dermal concentrations (ng/mL) of prilocaine will be measured to calculate the maximal dermal concentration (ng/mL). | 13 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood lidocaine concentrations versus time curve | Lidocaine concentrations (ng/mL) in the blood will be measured to obtain the concentration-time curves in the blood. | 13 hours | 
| Blood prilocaine concentrations versus time curve | Prilocaine concentrations (ng/mL) in the blood will be measured to obtain the concentration-time curves in the blood. | 13 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dermal open flow microperfusion