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Bioequivalence Evaluation of Topical Metronidazole Products Using Dermal Microdialysis in New Zealand Rabbits

  • Research Article
  • Novel Approaches for Cutaneous Pharmacokinetics
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Abstract

Comparative assessment of cutaneous pharmacokinetics (cPK) by dermal microdialysis (dMD) appears to be suitable to evaluate the bioequivalence (BE) of topical dermatological drug products applied to the skin (TDDPs). Although dMD studies in the literature have reported inconclusive BE assessments, we have addressed several methodological deficiencies to improve dMD’s capability to assess BE between reference (R) and approved generic (referred to as test (T)) gel and cream products of metronidazole (MTZ). The 90% confidence interval (CI) of the geometric mean ratios for the Ln(AUC0-24) and Ln(Cmax) endpoints was centered within the BE limits of 80–125%. The CIs extended outside this range as the proof-of-principle study was not statistically powered to demonstrate BE (N = 7 rabbits). A power analysis suggests that, with the variability observed in this study, 21 rabbits for the cream and 11 rabbits for the gel would be sufficient to support an evaluation of BE with the 2 probe replicates we used, and only 10 and 5 rabbits would be sufficient to power the study for the cream and gel, respectively, if 4 probe replicates are used for each treatment per rabbit. These results indicate that dMD when properly controlling variables can be used to support BE assessments for TDDPs.

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Data Availability

The data supporting this study’s findings are available from the corresponding author, GS, upon reasonable request.

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Acknowledgements

A great appreciation for the animal technician Cora Kaiser and the students (Mohammed Asif Ali, Andrew Litovsky, Rucha Pathak, Darshil Shah, and Morasa Sheikhy) that helped with the rabbit experiments. In addition, we appreciate the tremendous help from Dr. Kerry Weinberg, Director of Diagnostic Medical Sonography at LIU.

Funding

This project was supported by the Food and Drug Administration (FDA) of the U.S. Department of Health and Human Services (HHS) as part of an award (U01FD005862) totaling $750,000 with 100% funded by FDA/HHS.

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Author notes

  1. Benjamin A. Kuzma

    Present address: Drug Metabolism and Pharmacokinetics, Vertex Pharmaceuticals, Boston, Massachusetts, USA

Authors and Affiliations

  1. Division of Pharmaceutical Sciences, Arnold and Marie Schwartz College of Pharmacy, Long Island University, 75 DeKalb Ave., Brooklyn, New York, 11201, USA

    Sharareh Senemar, Benjamin A. Kuzma & Grazia Stagni

  2. 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

    Tannaz Ramezanli, Priyanka Ghosh & Sam G. Raney

  3. Division of Biometrics VIII, Office of Biostatistics, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, Maryland, USA

    Elena Rantou

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Contributions

Sharareh Senemar and Benjamin A. Kuzma: conceptualization, methodology, formal analysis, investigation, data curation, writing—review and editing; Tannaz Ramezanli, Priyanka Ghosh, and Sam G. Raney: conceptualization, methodology, formal analysis, writing—review and editing; Elena Rantou: bioequivalence data review analysis; Grazia Stagni: conceptualization, methodology, formal analysis, project administration, funding acquisition, writing—original draft, writing—review and editing.

Corresponding author

Correspondence to Grazia Stagni.

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The authors declare no competing interests.

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The views expressed in this paper do not reflect the official policies of the U.S. Food and Drug Administration or the U.S. Department of Health and Human Services; nor does any mention of trade names, commercial practices, or organization imply endorsement by the United States Government.

Additional information

Communicated by M. Alice Maciel Tabosa, Jaimin R. Shah, Sharareh Senemar, and Nisarg Modi.

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Senemar, S., Kuzma, B.A., Ramezanli, T. et al. Bioequivalence Evaluation of Topical Metronidazole Products Using Dermal Microdialysis in New Zealand Rabbits. AAPS PharmSciTech 24, 204 (2023). https://doi.org/10.1208/s12249-023-02660-2

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