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

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.

Study Overview

• Status: Completed
• Conditions: Healthy; Dermal Pharmacokinetic Measurements
• Intervention / Treatment: 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

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8010
    • CTU - Clinical Trials Unit, Medical University Graz

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 18 to 65 years inclusive.
2. Males and/or non-pregnant, non-breast feeding 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:

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: 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.

3. Diseases

   1. Congenital or idiopathic methemoglobinemia
   2. History of deep vein thrombosis (DVT)/pulmonary emboly (PE)
   3. Inherited blood disorders (such as factor V Leiden) who are prone to hypercoagulable state
   4. Glucose-6-phosphate dehydrogenase deficiencies
   5. Presence of any acute or chronic diseases 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, as 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.), as 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dermal Pharmacokinetic study; 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); Topical application; Other Names: Reference product; Drug: Lidocaine 2.5% and Prilocaine 2.5% cream (E. Fougera & Co. a division of Fougera Pharmaceuticals Inc., USA); Topical application; Other Names: Generic test product; Drug: Oraqix Parodontal-Gel (Dentsply Detrey GmbH, Germany); Topical application; Other Names: Non-equivalent test product; Device: Dermal open flow microperfusion; 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).; Procedure: Blood sampling; 1 sample will be taken pre-dose and 12 samples post-dose.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Joanneum Research Forschungsgesellschaft mbH

Publications and helpful links

General Publications

• Bodenlenz M, Tiffner KI, Raml R, Augustin T, Dragatin C, Birngruber T, Schimek D, Schwagerle G, Pieber TR, Raney SG, Kanfer I, Sinner F. Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clin Pharmacokinet. 2017 Jan;56(1):91-98. doi: 10.1007/s40262-016-0442-z. Erratum In: Clin Pharmacokinet. 2017 Jan;56(1):99.
• Bodenlenz M, Dragatin C, Liebenberger L, Tschapeller B, Boulgaropoulos B, Augustin T, Raml R, Gatschelhofer C, Wagner N, Benkali K, Rony F, Pieber T, Sinner F. Kinetics of Clobetasol-17-Propionate in Psoriatic Lesional and Non-Lesional Skin Assessed by Dermal Open Flow Microperfusion with Time and Space Resolution. Pharm Res. 2016 Sep;33(9):2229-38. doi: 10.1007/s11095-016-1960-y. Epub 2016 Jun 6.
• Bodenlenz M, Aigner B, Dragatin C, Liebenberger L, Zahiragic S, Hofferer C, Birngruber T, Priedl J, Feichtner F, Schaupp L, Korsatko S, Ratzer M, Magnes C, Pieber TR, Sinner F. Clinical applicability of dOFM devices for dermal sampling. Skin Res Technol. 2013 Nov;19(4):474-83. doi: 10.1111/srt.12071. Epub 2013 Apr 13.
• Dragatin C, Polus F, Bodenlenz M, Calonder C, Aigner B, Tiffner KI, Mader JK, Ratzer M, Woessner R, Pieber TR, Cheng Y, Loesche C, Sinner F, Bruin G. Secukinumab distributes into dermal interstitial fluid of psoriasis patients as demonstrated by open flow microperfusion. Exp Dermatol. 2016 Feb;25(2):157-9. doi: 10.1111/exd.12863. Epub 2015 Nov 23. No abstract available.
• Tiffner K, Boulgaropoulos B, Hofferer C, Birngruber T, Porksen N, Linnebjerg H, Garhyan P, Lam ECQ, Knadler MP, Pieber TR, Sinner F. Quantification of Basal Insulin Peglispro and Human Insulin in Adipose Tissue Interstitial Fluid by Open-Flow Microperfusion. Diabetes Technol Ther. 2017 May;19(5):305-314. doi: 10.1089/dia.2016.0384. Epub 2017 Mar 22.

Helpful Links

• In Vivo Dermal Open Flow Microperfusion: A Novel Approach to Evaluating Topical Bioavailability and Bioequivalence

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2019
• Primary Completion (Actual): December 15, 2019
• Study Completion (Actual): July 25, 2020

Study Registration Dates

• First Submitted: August 7, 2019
• First Submitted That Met QC Criteria: August 7, 2019
• First Posted (Actual): August 8, 2019

Study Record Updates

• Last Update Posted (Actual): October 12, 2020
• Last Update Submitted That Met QC Criteria: October 9, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Dermal open flow microperfusion
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Central Nervous System Depressants; Peripheral Nervous System Agents; Sensory System Agents; Anesthetics; Membrane Transport Modulators; Anesthetics, Local; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Lidocaine; Prilocaine
• Other Study ID Numbers: FDA02_AIM2_Main

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No