Cutaneous Pharmacokinetics of Acyclovir Cream 5% Products: Evaluating Bioequivalence with an In Vitro Permeation Test an
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RESEARCH PAPER
Cutaneous Pharmacokinetics of Acyclovir Cream 5% Products: Evaluating Bioequivalence with an In Vitro Permeation Test and an Adaptation of Scaled Average Bioequivalence Soo Hyeon Shin 1 & Elena Rantou 2 & Sam G. Raney 3 & Priyanka Ghosh 3 & Hazem Hassan 1,4 & Audra Stinchcomb 1 Received: 4 February 2020 / Accepted: 9 April 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Purpose The in vitro permeation test (IVPT) with a new statistical approach was investigated to evaluate the utility of an IVPT methodology as a sensitive tool to support a demonstration of bioequivalence (BE) for topical dermatological drug products. Methods IVPT experiments were performed utilizing ex vivo human skin. The initial screening tests involved four differently formulated acyclovir 5% creams: the U.S. Zovirax® as the reference product and the U.K. Zovirax®, Aciclovir 1A Pharma® and Aciclostad® as test products. Subsequently, a pivotal BE study was conducted comparing the two Zovirax® creams. The resulting data was used to evaluate BE of test (T) versus reference (R), T versus T, and R versus R, with an adaption of scaled average BE approach to address high variability in IVPT data. Results More acyclovir permeated into and through the skin from the two Zovirax® creams compared to the two nonZovirax® creams. The U.S. Zovirax® cream showed a significantly higher Jmax and total amount permeated over 48 h, compared to the U.K. Zovirax® cream. The statistical
Guest Editor: Sam Raney * Audra Stinchcomb [email protected] 1
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N. Pine Street PHN521, MD 21201 Baltimore, USA
2
Office of Biostatistics Office of Translational Sciences Center for Drug Evaluation and Research, United States Food and Drug Administration, White Oak Campus, MD Silver Spring, USA
3
Office of Research and Standards Office of Generic Drugs Center for Drug Evaluation and Research, United States Food and Drug Administration, MD 20993 Silver Spring, United States
4
Department of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy, Helwan University, Cairo, Egypt
analysis indicated that the test and reference products were not bioequivalent, whereas each product tested against itself was shown to be bioequivalent. Conclusions The current study demonstrated that the IVPT method, with an appropriate statistical analysis of the results, is a sensitive and discriminating test that can detect differences in the rate and extent of acyclovir bioavailability in the skin from differently formulated cream products.
KEY WORDS acyclovir . bioequivalence (BE) . in vitro permeation test (IVPT) . scaled average bioequivalence (SABE) . topical dermatological products
ABBREVIATIONS ABE AUC BA BE Cmax dOFM HPLC IVPT IVRT Jmax LLOQ PD PG PK Q1 Q2 Q3 QC R RLD
Average bioequivalence Area under the curve Bioavailability Bioequivalence Maximum concentration Dermal open flow microperfusion High performance liquid chromatography In vitro permea
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