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Cutaneous Pharmacokinetics of Acyclovir Cream 5% Products: Evaluating Bioequivalence with an In Vitro Permeation Test and an Adaptation of Scaled Average Bioequivalence

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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 non-Zovirax® 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 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.

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Abbreviations

ABE:

Average bioequivalence

AUC:

Area under the curve

BA:

Bioavailability

BE:

Bioequivalence

Cmax :

Maximum concentration

dOFM:

Dermal open flow microperfusion

HPLC:

High performance liquid chromatography

IVPT:

In vitro permeation test

IVRT:

In vitro release test

Jmax :

Maximum flux

LLOQ:

Lower limit of quantification

PD:

Pharmacodynamic

PG:

Propylene glycol

PK:

Pharmacokinetic

Q1:

Qualitatively

Q2:

Quantitatively

Q3:

Physically and structurally

QC:

Quality control

R:

Reference

RLD:

Reference Listed Drug

SABE:

Scaled average bioequivalence

SC:

Stratum corneum

T:

Test

TEWL:

Transepidermal water loss

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, 20 N. Pine Street PHN521, MD, 21201, Baltimore, USA

    Soo Hyeon Shin, Hazem Hassan & Audra Stinchcomb

  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

    Elena Rantou

  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

    Sam G. Raney & Priyanka Ghosh

  4. Department of Pharmaceutics and Industrial Pharmacy Faculty of Pharmacy, Helwan University, Cairo, Egypt

    Hazem Hassan

Authors
  1. Soo Hyeon Shin
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  2. Elena Rantou
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  3. Sam G. Raney
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  4. Priyanka Ghosh
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  5. Hazem Hassan
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  6. Audra Stinchcomb
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Correspondence to Audra Stinchcomb.

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Guest Editor: Sam Raney

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Shin, S., Rantou, E., Raney, S.G. et al. Cutaneous Pharmacokinetics of Acyclovir Cream 5% Products: Evaluating Bioequivalence with an In Vitro Permeation Test and an Adaptation of Scaled Average Bioequivalence. Pharm Res 37, 210 (2020). https://doi.org/10.1007/s11095-020-02821-z

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  • DOI: https://doi.org/10.1007/s11095-020-02821-z

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