Category: Clinical Pharmacology
Purpose: Techniques such as dermal microdialysis (dMD) and dermal open flow microperfusion (dOFM) can directly sample the dermal interstitial fluid and can characterize the cutaneous (dermal) pharmacokinetics (PK) of topically applied drug products. Therefore, dMD and dOFM may be useful to compare the rate and extent to which topically applied drugs become available in the skin from test and reference products. A convenient way to compare dermal PK is to dose the test and reference products in parallel at different skin sites on the same subject. However, topically applied drugs may be absorbed into the systemic circulation via dermal capillaries; highly permeable drugs, and/or those applied on large body surface areas may accumulate sufficiently in the systemic circulation to get redistributed back into the dermis (at all skin sites), which could increase “background” drug levels at all skin sites and may have the potential to confound the discrimination of dermal PK profiles between test and reference dosing sites. We performed a pilot study to develop a study design that could evaluate whether crosstalk occurs between the systemic and dermal PK. Specific aims were to verify whether the applied topical dose was systemically quantifiable (using blood draws) and/or influenced the dermal PK profiles (based upon “background” dermal PK profiles for lidocaine and prilocaine at non-dosed skin sites). Furthermore, dermal PK profiles were compared for 2 different doses, and the potential crosstalk between dosing sites (by lateral drug diffusion) was also evaluated.
Methods: Six healthy subjects were enrolled. Each subject had 9 test-sites (4 on each thigh, 1 on the upper arm). Two replicate sampling probes were inserted into the dermis of each test-site (Figure 1) and interstitial fluid was continuously sampled for 13 hours. dMD probes were inserted into 2 test-sites on the thigh and dOFM probes into the remaining 7 test-sites. After a baseline sample of 1 hour EMLA® (2.5% lidocaine; 2.5% prilocaine topical cream; Actavis Laboratories UT INC, US) was applied to test-sites on the thighs according to Figure 1. To achieve a sufficiently high bioavailability to have measurable systemic concentrations, an additional area on the abdomen was dosed with EMLA® and removed after 3 hours to gain a total dose of 60 g/400 cm² per subject. The dOFM test-site on the arm was non-dosed, and used to monitor potential redistribution of the drugs from the systemic circulation back into the dermis. In addition, the remaining dOFM test-site on the thigh was non-dosed, and used to assess any lateral diffusion from the adjacent, dosed test-sites, as well as any redistribution from the systemic circulation.
Additionally, blood samples were drawn in hourly intervals throughout the study to evaluate whether lidocaine or prilocaine were detectable in the systemic circulation. Lidocaine and prilocaine were quantified in Interstitial fluid and serum samples using high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS).
Results: A topical dose of 60 g of EMLA® per subject resulted in measurable concentrations of lidocaine and prilocaine in the systemic circulation as well as in the dermis at the non-dosed (re-distribution) test-site on the arm. At test-sites dosed with 150 mg/cm² of EMLA® cream, the dermal PK of lidocaine and prilocaine measured by dMD and dOFM were similar relative to each other (Figure 2).
Lidocaine and prilocaine concentrations measured in ISF samples at the low-dosed test-sites (15 mg/cm²) were more than 10 times lower than those at the high-dosed (150 mg/cm²) test-sites. Dermal concentrations of the non-dosed test-site on the arm (Cmax, Lidocaine= 23.43 ng/mL, Cmax, Prilocaine =38.00 ng/mL) and on the thigh (Cmax, Lidocaine= 27.63 ng/mL, Cmax, Prilocaine = 41.57 ng/mL) were comparable.
Conclusion: The applied dose of 60 g of EMLA® per subject was sufficiently high to facilitate the quantification of lidocaine and prilocaine in the systemic circulation and in the non-dosed sites due to redistribution of these drugs back into the skin at the non-dosed test-site on the arm. The distinct dermal PK profiles measured by dOFM at the test-sites dosed with low and high doses of EMLA® cream indicated that dOFM and dMD sampling techniques were sensitive to changes in dermal concentrations of lidocaine and prilocaine (Figure 2). The dermal concentrations at the non-dosed test-sites on the thigh (adjacent to dosed test-sites) were comparable to those at the non-dosed test-site on the arm, suggesting that lateral diffusion from the dosed test-sites was negligible, and indicating that the dermal PK profiles of lidocaine and prilocaine at the non-dosed test-sites are predominantly attributable to redistribution of these drugs from the systemic circulation back into the skin. Further research is warranted to evaluate the potential impact of the apparently negligible amount of systemic redistribution of drugs on the comparison of dermal PK profiles between test and reference topical products.
Katrin Tiffner– PhD Student, JOANNEUM RESEARCH Forschungsgesellschaft mbH HEALTH –Institute for Biomedicine and Health Sciences , Graz, Steiermark, Austria
Thomas Birngruber– HEALTH – Institute of Biomedicine and Health Sciences, JOANNEUM RESEARCH, Graz, Steiermark, Austria
Gerd Schwagerle– Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Steiermark, Austria
Tannaz Ramezanli– Pharmacologist, Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA, Silver Spring, Maryland
Manfred Bodenlenz– HEALTH – Institute of Biomedicine and Health Sciences, JOANNEUM RESEARCH, Graz, Steiermark, Austria
Bettina Lackner– Graz, Steiermark, Austria
Thomas Augustin– HEALTH – Institute of Biomedicine and Health Sciences, JOANNEUM RESEARCH, Graz, Steiermark, Austria
Reingard Raml– HEALTH – Institute of Biomedicine and Health Sciences, JOANNEUM RESEARCH, Graz, Steiermark, Austria
Isadore Kanfer– Emeritus Professor, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Sam Raney– Lead for Topical & Transdermal Drug Products, U.S. FDA, Silver Spring, Maryland
Frank Sinner– Graz, Steiermark, Austria