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Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence.
Clin Pharmacokinet. 2017 01; 56(1):91-98.CP

Abstract

BACKGROUND

The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products.

OBJECTIVE

To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product.

METHODS

In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum dermal concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80-1.25.

RESULTS

The positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent.

CONCLUSIONS

dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study).

Links

Authors+Show Affiliations

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria.

Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria. Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.

Division of Therapeutic Performance, Office of Research and Standards, Office of Generic Drugs, US Food and Drug Administration, Silver Spring, MD, USA.

Faculty of Pharmacy, Rhodes University, Grahamstown, South Africa. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.

HEALTH-Institute for Biomedicine and Health Sciences, Joanneum Research Forschungsgesellschaft mbH, Neue Stiftingtalstrasse 2, 8010, Graz, Austria. frank.sinner@joanneum.at. Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria. frank.sinner@joanneum.at.

MeSH

AcyclovirAdministration, CutaneousAdultAntiviral AgentsArea Under CurveFemaleHumansMaleMicrodialysisSkin CreamTherapeutic Equivalency

Pub Type(s)

Journal Article

Randomized Controlled Trial

Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

27539717

Clinical Trial Links

An Exploratory Pilot Study in Healthy Volunteers to Assess the Parameters for the Design of Bioequivalence Studies on Moderately Lipophilic, Moderately to Highly Protein Bound Drugs Using Dermal Open Flow Microperfusion (dOFM)

An Exploratory Study in Healthy Volunteers to Identify Factors Influencing Bioequivalence Studies on Moderately Lipophilic Drugs Using Dermal Open Flow Microperfusion (dOFM)

An Exploratory Study in Healthy Volunteers to Investigate the Cross-talk Between Local Drug Concentrations in the Skin and Systemic Concentrations During Topical Bioequivalence Studies Using Dermal Sampling Techniques

Evaluate the Ability of dOFM for BE Testing of Topically Applied Diclofenac Sodium Products in Healthy Subjects

Citation

Bodenlenz, Manfred, et al. "Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence." Clinical Pharmacokinetics, vol. 56, no. 1, 2017, pp. 91-98.

Bodenlenz M, Tiffner KI, Raml R, et al. Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clin Pharmacokinet. 2017;56(1):91-98.

Bodenlenz, M., Tiffner, K. I., Raml, R., Augustin, T., Dragatin, C., Birngruber, T., Schimek, D., Schwagerle, G., Pieber, T. R., Raney, S. G., Kanfer, I., & Sinner, F. (2017). Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clinical Pharmacokinetics, 56(1), 91-98. https://doi.org/10.1007/s40262-016-0442-z

Bodenlenz M, et al. Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. Clin Pharmacokinet. 2017;56(1):91-98. PubMed PMID: 27539717.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Open Flow Microperfusion as a Dermal Pharmacokinetic Approach to Evaluate Topical Bioequivalence. AU - Bodenlenz,Manfred, AU - Tiffner,Katrin I, AU - Raml,Reingard, AU - Augustin,Thomas, AU - Dragatin,Christian, AU - Birngruber,Thomas, AU - Schimek,Denise, AU - Schwagerle,Gerd, AU - Pieber,Thomas R, AU - Raney,Sam G, AU - Kanfer,Isadore, AU - Sinner,Frank, PY - 2016/8/20/pubmed PY - 2017/8/17/medline PY - 2016/8/20/entrez SP - 91 EP - 98 JF - Clinical pharmacokinetics JO - Clin Pharmacokinet VL - 56 IS - 1 N2 - BACKGROUND: The availability of generic topical dermatological drug products is constrained by the limited methods established to assess topical bioequivalence (BE). A novel cutaneous pharmacokinetic approach, dermal open-flow microperfusion (dOFM), can continuously assess the rate and extent to which a topical drug becomes available in the dermis, to compare in vivo dermal bioavailability (BA) and support BE evaluations for topical products. OBJECTIVE: To evaluate whether dOFM is an accurate, sensitive, and reproducible in vivo method to characterize the intradermal BA of acyclovir from 5 % acyclovir creams, comparing a reference (R) product either to itself or to a different test (T) product. METHODS: In a single-center clinical study, R or T products were applied to six randomized treatment sites on the skin of 20 healthy human subjects. Two dOFM probes were inserted in each treatment site to monitor the intradermal acyclovir concentration for 36 h. Comparative BA (of R vs. R and T vs. R) was evaluated based on conventional BE criteria for pharmacokinetic endpoints (area under the curve and maximum dermal concentration) where the 90 % confidence interval of the geometric mean ratio between the T and R falls within 0.80-1.25. RESULTS: The positive control products (R vs. R) were accurately and reproducibly confirmed to be bioequivalent, while the negative control products (T vs. R) were sensitively discriminated not to be bioequivalent. CONCLUSIONS: dOFM accurately, sensitively, and reproducibly characterized the dermal BA in a manner that can support BE evaluations for topical acyclovir 5 % creams in a study with n = 40 (20 subjects in this study). SN - 1179-1926 UR - https://www.unboundmedicine.com/medline/citation/27539717/Open_Flow_Microperfusion_as_a_Dermal_Pharmacokinetic_Approach_to_Evaluate_Topical_Bioequivalence_ DB - PRIME DP - Unbound Medicine ER -