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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
6
* Each subject will have 9 test sites: 4 on the left thigh, 4 on the right thigh, 1 on the arm * Each test site receives 2 dOFM probes * Dosing: * 2 test sites: 15 mg/cm² lidocaine and prilocaine cream (2.5% lidocaine, 2.5% prilocaine, ACTAVIS LABORATORIES UT INC, US) * 2 test sites: 10 mg/cm² lidocaine and prilocaine cream (2.5% lidocaine, 2.5% prilocaine, ACTAVIS LABORATORIES UT INC, US) * 2 test sites: 5 mg/cm² lidocaine and prilocaine cream (2.5% lidocaine, 2.5% prilocaine, ACTAVIS LABORATORIES UT INC, US) * 1 test site: 10 mg/cm² Oraqix® gel (2.5% lidocaine, 2.5% prilocaine, Dentsply Pharmaceutical Inc., US/Dentsply DETRY GmbH, Germany) * 2 test sites: untreated test site * ISF sampling: 24 hours post-dose * Blood sampling: 7 samples post-dose
lidocaine and prilocaine cream (2.5% lidocaine, 2.5% prilocaine, ACTAVIS LABORATORIES UT INC, US) will be applied to 6 test sites per subject
Oraqix® gel (2.5% lidocaine, 2.5% prilocaine, Dentsply Pharmaceutical Inc., US/Dentsply DETRY GmbH, Germany) will be applied to 1 test site per subject
Dermal open flow microperfusion system will be used to collect interstitial fluid in order to assess lidocaine/prilocaine concentrations over 24 hours
8 blood samples will be collected in order to assess systemic lidocaine/prilocaine concentrations pre-dose (1 sample) and 24 hours post dose (7 samples)
HEALTH - Joanneum Research
Graz, Austria
Find the dose of Lidocaine 2.5% and Prilocaine 2.5% cream for the main study by comparing the concentration time curves and corresponding PK parameter Cmax of 3 different doses (5 mg/cm², 10 mg/cm² and 15 mg/cm²) twice in each subject
Three different doses (5 mg/cm², 10 mg/cm² and 15 mg/cm²) of Lidocaine 2.5% and Prilocaine 2.5% cream will be dosed twice in each subject in parallel. The concentration time curves and the PK parameter Cmax of this three doses will be compared and based on this data the team will decide in collaboration with the FDA project officer which dose will be used for the main study. Thereby study duration and sampling intervals (resolution) for the main study will be defined.
Time frame: 24 hours
Find the dose of Lidocaine 2.5% and Prilocaine 2.5% cream for the main study by comparing the concentration time curves and corresponding PK parameter AUC of 3 different doses (5 mg/cm², 10 mg/cm² and 15 mg/cm²) twice in each subject
Three different doses (5 mg/cm², 10 mg/cm² and 15 mg/cm²) of Lidocaine 2.5% and Prilocaine 2.5% cream will be dosed twice in each subject in parallel. The concentration time curves and the PK parameter AUC of this three doses will be compared and based on this data the team will decide in collaboration with the FDA project officer which dose will be used for the main study. Thereby study duration and sampling intervals (resolution) for the main study will be defined.
Time frame: 24 hours
Test for systemic exposure and systemic cross-talk by measuring lidocaine/prilocaine concentrations (µg/ml) in blood samples and ISF samples from a distant untreated test site on the arm
To measure the degree to which lidocaine and/or prilocaine are absorbed into the skin and are redistributed via the blood stream. Lidocaine and Prilocaine concentrations will be measured in blood samples and ISF samples from a distant untreated test site on the arm. If no significant drug concentration are found in the blood samples and in the skin of the untreated topical test site on the arm (relative to the drug concentration of the treated sites) systemic exposure can be excluded.
Time frame: 24 hours
Test for lateral diffusion (crosstalk between adjacent test sites) by measuring lidocaine/prilocaine concentrations (µg/ml) of untreated test sites
In one central control site, located between two test sites dosed with lidocaine and prilocaine cream, no drug product will be applied. This setup allows testing for lateral diffusion in the skin. If no significant lidocaine or prilocaine concentration (relative to the drug concentration of the treated sites) in combination with the results from outcome 2 can be found in this untreated test site, lateral diffusion can be excluded.
Time frame: 24 hours
Check if Oraqix® gel can be used as 'negative control' for bioequivalence testing in the main study by comparing Oraqix® gel with Lidocaine and prilocaine cream (AUC).
On one test site Oraqix® gel will be applied with a dose of 10 mg/cm² and on another test site lidocain and prilocaine crem will be applied with a dose of 10 mg/cm². Oraqix® gel will be compared with lidocaine and prilocaine cream by performing the average bioequivalence test. In accordance with the CDER-Guidance on "Statistical approaches on establishing bioequivalence", the 90% confidence interval for the mean difference of the AUC values will be calculated. Oraqix® gel can be used as 'negative control' if the calculated confidence interval dose not fall within the limits of 0.80 - 1.25.
Time frame: 24 hours
Check if Oraqix® gel can be used as 'negative control' for bioequivalence testing in the main study by comparing Oraqix® gel with Lidocaine and prilocaine cream (Cmax).
On one test site Oraqix® gel will be applied with a dose of 10 mg/cm² and on another test site lidocain and prilocaine crem will be applied with a dose of 10 mg/cm². Oraqix® gel will be compared with lidocaine and prilocaine cream by performing the average bioequivalence test. In accordance with the CDER-Guidance on "Statistical approaches on establishing bioequivalence", the 90% confidence interval for the mean difference of the Cmax values will be calculated. Oraqix® gel can be used as 'negative control' if the calculated confidence interval dose not fall within the limits of 0.80 - 1.25.
Time frame: 24 hours
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