Pharmaceutical Research

, 26:316 | Cite as

Improved Bioequivalence Assessment of Topical Dermatological Drug Products Using Dermatopharmacokinetics

  • Berthe N’Dri-Stempfer
  • William C. Navidi
  • Richard H. Guy
  • Annette L. Bunge
Research Paper

Abstract

Purpose

A dermatopharmacokinetic (DPK) approach, in which drug levels in the stratum corneum (SC) are measured as a function of time post-application and post-removal of the product using tape-strip sampling in vivo in humans, has been considered for the comparative assessment of topical bioavailability. Its application to-date has been limited by contradictory results and concerns that variability in the method necessitates large numbers of treatment sites and volunteers. The objective of this study was to test whether a revised protocol could better assess bioequivalence.

Methods

A blinded study of three 1% econazole nitrate cream products, for which the SC is the site of action, was conducted to examine several modifications to the DPK methodology. In addition to protocol changes designed to reduce experimental variability, bioequivalence was assessed at a single uptake time and a single clearance time measured in duplicate in each subject.

Results

Conclusive determinations of bioequivalence were achieved with only four treatment sites per product in each of 14 volunteers, which was less than one-third the number required in a previous DPK investigation.

Conclusions

Comparative bioequivalence can be assessed conclusively with fewer treatment sites in fewer subjects with robust methods that should be less sensitive to inter-laboratory differences.

KEY WORDS

dermatopharmacokinetics econazole skin stratum corneum tape stripping topical drug bioequivalence 

References

  1. 1.
    US FDA. Guidance for Industry: topical dermatological drug product NDAs and ANDAs-in vivo bioavilability, bioequivalence, in vitro release, and associated studies. Draft Guidance, June 1998, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), (1998).Google Scholar
  2. 2.
    US FDA. Guidance for industry on special protocol assessment; availability. Fed. Regist. 67:35122 (2002).Google Scholar
  3. 3.
    L. K. Pershing. Bioequivalence assessment of three 0.025% tretinoin gel products: Dermatopharmacokinetic vs. Clinical Trial Methods, Transcribed presentation to the Advisory Committee for Pharmaceutical Sciences Meeting, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Rockville, MD, November 29, 2001; presentation slides available at http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s2_02_Pershing/index.htm; transcript of presentation available at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2_01_Morning_Session.pdf pp. 31–47
  4. 4.
    T. J. Franz. Study #1, Avita Gel 0.025% vs Retin-A Gel 0.025%, Transcribed presentation, Advisory Committee for Pharmaceutical Sciences Meeting, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Rockville, MD, November 29, 2001; presentation slides available at http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s2_03_franz.pdf transcript of presentation available at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/ 3804t2_01_Morning_Session.pdf pp. 47–61
  5. 5.
    D. P. Conner. Differences in DPK Methods, Transcribed presentation to the Advisory Committee for Pharmaceutical Sciences Meeting, Center for Drug Evaluation and Research (CDER), Food and Drug Administration (FDA), Rockville, MD, November 29, 2001; presentation slides available at http://www.fda.gov/ohrms/dockets/ac/01/slides/3804s2_05_conner/index.htm; transcript of presentation available at http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3804t2_01_Morning_Session.pdf, pp 71–75
  6. 6.
    A. L. Bunge, B. N’Dri-Stempfer, W. C. Navidi, and R. H. Guy. Dermatopharmacokinetics: improvement of methodology for assessing bioequivalence of topical dermatological drug products, Revised Final Report, Award No. D3921303, Submitted to Department of Health and Human Services, Food and Drug Administration, Colorado School of Mines, Golden, CO, September 2, 2006.Google Scholar
  7. 7.
    A. L. Bunge, B. N’Dri-Stempfer, W. C. Navidi, and R. H. Guy. Therapeutic Equivalence of Topical Products, Final Report, Award No. 223-04-3004, Submitted to Department of Health and Human Services, Food and Drug Administration, Colorado School of Mines, Golden, CO, January 30, 2007 (Revision submitted June 2008).Google Scholar
  8. 8.
    W. Navidi, A. Hutchinson, B. N’Dri-Stempfer, and A. L. Bunge. Determining bioequivalence of topical dermatological products by tape-stripping. J. Pharmacokin. Pharmacodyn. Article in press, doi:10:1007/s10928-008-9091-7 (2008).
  9. 9.
    B. N’Dri-Stempfer, W. C. Navidi, R. H. Guy, and A. L. Bunge. Optimizing metrics for the assessment of bioequivalence between topical drug products. Pharm. Res. 25:1621–1630 (2008) Medline. doi:10.1007/s11095-008-9577-4.PubMedCrossRefGoogle Scholar
  10. 10.
    L. K. Pershing. Final Report to Food and Drug Administration (FDA): Dermatopharmacokinetic Bioequivalence Study on Three Tretinoin Gel, 0.025% Products, University of Utah, Salt Lake City, 2000.Google Scholar
  11. 11.
    L. K. Pershing, J. L. Corlett, and J. L. Nelson. Comparison of dermatopharmacokinetic vs. clinical efficacy methods for bioequivalence assessment of miconazole nitrate vaginal cream, 2% in humans. Pharm. Res. 19:270–277 (2002) Medline. doi:10.1023/A:1014486716823.PubMedCrossRefGoogle Scholar
  12. 12.
    Y. N. Kalia, I. Alberti, N. Sekkat, C. Curdy, A. Naik, and R. H. Guy. Normalization of stratum corneum barrier function and transepidermal water loss in vivo. Pharm. Res. 17:1148–1150 (2000) Medline. doi:10.1023/A:1026474200575.PubMedCrossRefGoogle Scholar
  13. 13.
    L. M. Russell, S. Wiedersberg, and M. B. Delgado-Charro. The determination of stratum corneum thickness—an alternative approach. Eur J Pharm Biopharm 69:861–870. doi:10.1016/j.ejpb.2008.02.002 (2008).Google Scholar
  14. 14.
    C. Pellanda, E. Ottiker, C. Strub, V. Figueiredo, T. Rufli, G. Imanidis, and C. Surber. Topical bioavailability of triamcinolone acetonide: effect of dose and application frequency. Arch. Dermatol. Res. 298:221–230 (2006) Medline. doi:10.1007/s00403-006-0677-x.PubMedCrossRefGoogle Scholar
  15. 15.
    I. Jakasa, M. M. Verberk, A. L. Bunge, J. Kruse, and S. Kezic. Increased permeability for polyethylene glycols through skin compromised by sodium lauryl sulphate. Exp. Dermatol. 15:801–807 (2006) Medline. doi:10.1111/j.1600-0625.2006.00478.x.PubMedCrossRefGoogle Scholar
  16. 16.
    H.-J. Weigmann, U. Lindemann, C. Antoniou, G. N. Tsikrikas, A. I. Stratigos, A. Katsambas, W. Sterry, and J. Lademann. UV/VIS absorbance allows rapid, accurate, and reproducible mass determination of corneocytes removed by tape stripping. Skin Pharmcol. Appl. Skin Physiol. 16:217–227 (2003) Medline. doi:10.1159/000070844.CrossRefGoogle Scholar
  17. 17.
    U. Lindemann, H.-J. Weigmann, H. Schaefer, and W. Sterry. Evaluation of the pseudo-absorption method to quantify human stratum corneum removed by tape stripping using protein absorption. Skin Pharmcol. Appl. Skin Physiol. 16:228–236 (2003) Medline. doi:10.1159/000070845.CrossRefGoogle Scholar
  18. 18.
    L. K. Pershing, S. Bakhtian, C. E. Poncelet, J. L. Corlett, and V. P. Shah. Comparison of skin stripping, in vitro release, and skin blanching response methods to measure dose response and similarity of triamcinolone actonide cream strengths from two manufactured sources. J. Pharm. Sci. 91:1312–1323 (2002) Medline. doi:10.1002/jps.10147.PubMedCrossRefGoogle Scholar
  19. 19.
    F. Pirot, Y. N. Kalia, A. L. Stinchcomb, G. Keating, A. Bunge, and R. H. Guy. Characterization of the permeability barrier of human skin in vivo. Proc. Nat. Acad. Sci. USA. 94:1562–1567 (1997) Medline. doi:10.1073/pnas.94.4.1562.PubMedCrossRefGoogle Scholar
  20. 20.
    F. Dreher, A. Arens, J. J. Hostynek, S. Mudumba, J. Ademola, and H. I. Maibach. Colorimetric method for quantifying stratum corneum removed by adhesive-tape stripping. Acta. Derm. Venereol. (Stockh). 78:186–189 (1998). doi:10.1080/000155598441495.CrossRefGoogle Scholar
  21. 21.
    L. K. Pershing, J. L. Nelson, J. L. Corlett, S. P. Shrivastave, D. B. Hare, and V. P. Shah. Assessment of dermatopharmacokinetic approach in the bioequivalence determination of topical tretinoin gel products. J. Am. Acad. Dermatol. 48:740–751 (2003) Medline. doi:10.1067/mjd.2003.175.PubMedCrossRefGoogle Scholar
  22. 22.
    US FDA. Approved drug products with therapeutic equivalence evaluations (Electronic Orange Book), U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Office of Pharmaceutical Science, Office of Generic Drugs, http://www.fda.gov/cder/orange/obannual.pdf (2007).
  23. 23.
    Y. N. Kalia, F. Pirot, and R. H. Guy. Homogeneous transport in a heterogeneous membrane: Water diffusion across human stratum corneum in vivo. Biophys. J. 71:2692–2700 (1996).PubMedCrossRefGoogle Scholar
  24. 24.
    US EPA. Assessing Values to Non-Detected/Non-Quantified Pesticide Residues in Human Health Food Exposure Assessments, Guidance Document: Office of Pesticide Programs, (March 23, 2000), Washington, DC, http://www.epa.gov/pesticides/trac/science/trac3b012.pdf, 2000.
  25. 25.
    V. R. Meyer. Practical high-performance liquid chromatography. Wiley, West Sussex, England, 1994.Google Scholar
  26. 26.
    J. Corley. Best practice in establishing detection and quantification limits for pesticide residues in foods. In P. W. Lee (ed.), Handbook of Residue Analytical Methods for Agrochemicals, Volumes 1–2, Wiley, West Sussex, England, 2003.Google Scholar
  27. 27.
    R. Christinat, and H. W. Zulliger. Stability indicating HPLC-method for the determination of econazole nitrate in cream and lotion formulations. Arzneimittel. forschung/Drug Res. 34:551–553 (1984).Google Scholar
  28. 28.
    P. A. Cornwell, and B. W. Barry. Effects of penetration enhancer treatment on the statistical distribution of human skin permeabilities. Int. J. Pharm. 117:101–112 (1995). doi:10.1016/0378-5173(94)00341-2.CrossRefGoogle Scholar
  29. 29.
    A. C. Williams, P. A. Cornwell, and B. W. Barry. On the non-Gaussian distribution of human skin permeabilities. Int. J. Pharm. 86:69–77 (1992). doi:10.1016/0378-5173(92)90032-W.CrossRefGoogle Scholar
  30. 30.
    G. B. Kasting, T. G. Filloon, W. R. Francis, and M. P. Meredith. Improving the sensitivity of in vitro skin penetration experiments. Pharm. Res. 11:1747–1754 (1994) Medline. doi:10.1023/A:1018915416930.PubMedCrossRefGoogle Scholar
  31. 31.
    D. J. Schuirmann. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J. Pharmacokinet. Biopharm. 15:657–680 (1987) Medline. doi:10.1007/BF01068419.PubMedCrossRefGoogle Scholar
  32. 32.
    G. E. P. Box, and D. R. Cox. An analysis of transformations. J. R. Stat. Soc., Series B. 26:211–252 (1964).Google Scholar
  33. 33.
    A. L. Bunge, R. L. Cleek, and B. E. Vecchia. A new method for estimating dermal absorption from chemical exposure. 3. Compared with steady-state methods for prediction and data analysis. Pharm. Res. 12:972–982 (1995) Medline. doi:10.1023/A:1016298012408.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Berthe N’Dri-Stempfer
    • 1
    • 4
  • William C. Navidi
    • 2
  • Richard H. Guy
    • 3
  • Annette L. Bunge
    • 1
  1. 1.Chemical Engineering DepartmentColorado School of MinesGoldenUSA
  2. 2.Mathematical and Computer Science DepartmentColorado School of MinesGoldenUSA
  3. 3.Department of Pharmacy & PharmacologyUniversity of BathBathUnited Kingdom
  4. 4.Array BioPharmaLongmontUSA

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