Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfu
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RESEARCH PAPER
Variability of Skin Pharmacokinetic Data: Insights from a Topical Bioequivalence Study Using Dermal Open Flow Microperfusion Manfred Bodenlenz 1 & Thomas Augustin 1 & Thomas Birngruber 1 & Katrin I. Tiffner 1 & Beate Boulgaropoulos 1,2 & Simon Schwingenschuh 1 & Sam G. Raney 3 & Elena Rantou 4 & Frank Sinner 1,2
Received: 28 May 2020 / Accepted: 28 August 2020 # The Author(s) 2020
ABSTRACT Purpose Dermal open flow microperfusion (dOFM) has previously demonstrated its utility to assess the bioequivalence (BE) of topical drug products in a clinical study. We aimed to characterize the sources of variability in the dermal pharmacokinetic data from that study. Methods Exploratory statistical analyses were performed with multivariate data from a clinical dOFM-study in 20 healthy adults evaluating the BE, or lack thereof, of Austrian test (T) and U.S. reference (R) acyclovir cream, 5% products. Results The overall variability of logAUC values (CV: 39% for R and 45% for T) was dominated by inter-subject variability (R: 82%, T: 91%) which correlated best with the subject’s skin conductance. Intra-subject variability was 18% (R) and 9% (T) of the overall variability; skin treatment sites or methodological factors did not significantly contribute to that variability. Conclusions Inter-subject variability was the major component of overall variability for acyclovir, and treatment site location did not significantly influence intra-subject variability. Guest Editor: Sam Raney * Frank Sinner [email protected]
These results support a dOFM BE study design with T and R products assessed simultaneously on the same subject, where T and R treatment sites do not necessarily need to be next to each other. Localized variation in skin microstructure may be primarily responsible for intra-subject variability.
KEY WORDS Topical bioequivalence . inter- and intra-subject variability . dermal open flow microperfusion . microdialysis . acyclovir . skin pharmacokinetics
ABBREVIATIONS ANOVA AUC BE BMI Cmax CV dMD dOFM FDA
analysis of variance Area under the dermal concentration-time curve bioequivalence body mass index maximum dermal concentration % coefficient of variation dermal microdialysis dermal open flow microperfusion United States Food and Drug Administration log-transformed AUC values log-transformed Cmax values pharmacokinetics reference product test product transepidermal water loss United States
1
HEALTH - Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft m.b.H, Neue Stiftingtalstrasse 2, 8010 Graz, Austria
2
Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Auenbruggerplatz 15, 8036 Graz, Austria
logAUC values logCmax PK R T TEWL U.S.
3
Division of Therapeutic Performance Office of Research and Standards Office of Generic Drugs, United States (U.S.) Food and Drug Administration, 10903 New Hampshire Avenue, MD 20993 Silver Spring, USA
INTRODUCTION
Division of Biostatistics VIII, Office of Biostatistics, Office
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