Skip to main content

Advertisement

SpringerLink
Log in

Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies

  • RESEARCH PAPER
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To investigate the difference in clinical efficacy in AD patients between two topical PDE4 inhibitors using dermal open flow microperfusion and cAMP as a pharmacodynamic read-out in fresh human skin explants.

Methods

Clinical formulations were applied to intact or barrier disrupted human skin explants and both skin biopsy samples and dermal interstitial fluid was sampled for measuring drug concentration. Furthermore, cAMP levels were determined in the skin biopsies as a measure of target engagement.

Results

Elevated cAMP levels were observed with LEO 29102 while no evidence of target engagement was obtained with LEO 39652. In barrier impaired skin the dISF concentration of LEO 29102 was 2100 nM while only 33 nM for LEO 39652. For both compounds the concentrations measured in skin punch biopsies were 7–33-fold higher than the dISF concentrations.

Conclusions

Low unbound drug concentration in dISF in combination with minimal target engagement of LEO 39652 in barrier impaired human skin explants supports that lack of clinical efficacy of LEO 39652 in AD patients is likely due to insufficient drug availability at the target. We conclude that dOFM together with a pharmacodynamic target engagement biomarker are strong techniques for establishing skin PK/PD relations and that skin biopsies should be used with caution.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

AD:

Atopic dermatitis

cAMP:

Cyclic adenosine monophosphate

dISF:

Dermal interstitial fluid concentration

dOFM:

Dermal open flow microperfusion

HSA:

Human serum albumin

MD:

Microdialysis

PDE4:

Phosphodiesterase 4

PK/PD:

Pharmacokinetic / Pharmacodynamic

References

  1. Nutten S. Atopic dermatitis: global epidemiology and risk factors. Ann Nutr Metab. 2015;66(Suppl 1):8–16.

    Article  CAS  Google Scholar 

  2. Boguniewicz M, Fonacier L, Guttman-Yassky E, Ong PY, Silverberg J, Farrar JR. Atopic dermatitis yardstick: Practical recommendations for an evolving therapeutic landscape. Ann Allergy Asthma Immunol. 2018;120(1):10–22.e2.

    Article  Google Scholar 

  3. Atherton DJ. Topical corticosteroids in atopic dermatitis. Bmj. 2003;327(7421):942–3.

    Article  Google Scholar 

  4. Carr WW. Topical calcineurin inhibitors for atopic dermatitis: review and treatment recommendations. Paediatr Drugs. 2013;15(4):303–10.

    Article  Google Scholar 

  5. Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, et al. Dupilumab treatment in adults with moderate-to-severe atopic dermatitis. N Engl J Med. 2014;371(2):130–9.

    Article  Google Scholar 

  6. Jarnagin K, Chanda S, Coronado D, Ciaravino V, Zane LT, Guttman-Yassky E, et al. Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory Phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis. J Drugs Dermatol. 2016;15(4):390–6.

    CAS  PubMed  Google Scholar 

  7. Simpson EL, Imafuku S, Poulin Y, Ungar B, Zhou L, Malik K, et al. A phase 2 randomized trial of Apremilast in patients with atopic dermatitis. J Invest Dermatol. 2019;139(5):1063–72.

    Article  CAS  Google Scholar 

  8. Felding J, Sørensen MD, Poulsen TD, Larsen J, Andersson C, Refer P, et al. Discovery and early clinical development of 2-(1)-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis. J Med Chem. 2014;57(14):5893–903.

    Article  CAS  Google Scholar 

  9. Larsen J, Lambert M, Pettersson H, Vifian T, Larsen M, Ollerstam A, et al. (2020) Discovery and Early Clinical Development of Isobutyl 1-[8-Methoxy-5-(1-oxo-3H-isobenzofuran-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxylate (LEO 39652), a Novel “Dual-Soft” PDE4 Inhibitor for Topical Treatment of Atopic Dermatitis. J Med Chem. https://doi.org/10.1021/acs.jmedchem.0c00797.

  10. Clinical Study Report Synopsis. LEO 29102 Cream in the Treatment of Atopic Dermatitis. A Phase 2, proof of concept and dose finding study, investigating treatment efficacy of LEO 29102 cream (2.5 mg/g, 1.0 mg/g, 0.3 mg/g, 0.1 mg/g, 0.03 mg/g), LEO 29102 cream vehicle, and Elidel® (pimecrolimus) cream 10 mg/g, after cutaneous administration twice daily for 4 weeks. 2011 March 31. Available from: https://www.clinicaltrialsregister.eu/ctr-search/rest/download/result/attachment/2009-013792-22/1/17100. Accessed 1 May 2020.

  11. Clinical Study Report. An Explorative Trial Evaluating the Effect of LEO 39652 Cream 2.5 mg/g in Adults with Mild to Moderate Atopic Dermatitis (AD) A phase I, single-centre, prospective, randomised, vehicle-controlled, double-blind, intraindividual comparison trial with twice daily topical administration for 3 weeks.2015 August 19. Available from: https://www.leoclinicaltrials.com/Frontpage/Our%20clinical%20trials/Trial%20page/?lpNumber=LP0083-1085. Accessed 1 May 2020.

  12. Herkenne C, Alberti I, Naik A, Kalia YN, Mathy FX, Préat V, et al. In vivo methods for the assessment of topical drug bioavailability. Pharm Res. 2008;25(1):87–103.

    Article  CAS  Google Scholar 

  13. Holmgaard R, Benfeldt E, Nielsen JB, Gatschelhofer C, Sorensen JA, Höfferer C, et al. Comparison of open-flow microperfusion and microdialysis methodologies when sampling topically applied fentanyl and benzoic acid in human dermis ex vivo. Pharm Res. 2012;29(7):1808–20.

    Article  CAS  Google Scholar 

  14. Altendorfer-Kroath T, Schimek D, Eberl A, Rauter G, Ratzer M, Raml R, et al. Comparison of cerebral open flow microperfusion and microdialysis when sampling small lipophilic and small hydrophilic substances. J Neurosci Methods. 2019;311:394–401.

    Article  CAS  Google Scholar 

  15. Bodenlenz M, Dragatin C, Liebenberger L, Tschapeller B, Boulgaropoulos B, Augustin T, et al. Kinetics of Clobetasol-17-propionate in psoriatic Lesional and non-Lesional skin assessed by dermal open flow microperfusion with time and space resolution. Pharm Res. 2016;33(9):2229–38.

    Article  CAS  Google Scholar 

  16. Bodenlenz M, Tiffner KI, Raml R, Augustin T, Dragatin C, Birngruber T, et al. Open flow microperfusion as a dermal pharmacokinetic approach to evaluate topical bioequivalence. Clin Pharmacokinet. 2017;56(1):91–8.

    Article  CAS  Google Scholar 

  17. Halling-Overgaard AS, Kezic S, Jakasa I, Engebretsen KA, Maibach H, Thyssen JP. Skin absorption through atopic dermatitis skin: a systematic review. Br J Dermatol. 2017;177(1):84–106.

    Article  Google Scholar 

  18. Liu X, Wright M, Hop CE. Rational use of plasma protein and tissue binding data in drug design. J Med Chem. 2014;57(20):8238–48.

    Article  CAS  Google Scholar 

  19. Aukland K, Reed RK. Interstitial-lymphatic mechanisms in the control of extracellular fluid volume. Physiol Rev. 1993;73(1):1–78.

    Article  CAS  Google Scholar 

  20. Efron B, Tibshirani R. Bootstrap methods for standard errors, confidence intervals, and other measures of statistical accuracy. Stat Sci. 1986;1(1):54–75.

    Article  Google Scholar 

  21. Sørensen IS, Janfelt C, Nielsen MMB, Mortensen RW, Knudsen N, Eriksson AH, et al. Combination of MALDI-MSI and cassette dosing for evaluation of drug distribution in human skin explant. Anal Bioanal Chem. 2017;409(21):4993–5005.

    Article  Google Scholar 

  22. Bodenlenz M, Höfferer C, Magnes C, Schaller-Ammann R, Schaupp L, Feichtner F, et al. Dermal PK/PD of a lipophilic topical drug in psoriatic patients by continuous intradermal membrane-free sampling. Eur J Pharm Biopharm. 2012;81(3):635–41.

    Article  CAS  Google Scholar 

  23. Garcia Ortiz P, Hansen SH, Shah VP, Menné T, Benfeldt E. Impact of adult atopic dermatitis on topical drug penetration: assessment by cutaneous microdialysis and tape stripping. Acta Derm Venereol. 2009;89(1):33–8.

    Article  CAS  Google Scholar 

Download references

Acknowledgments and Disclosures

The authors would like to thank scientific and technical staff in the Research and Pharmaceutical Design and Development area of LEO Pharma for their dedicated support with synthesis, analysis and preparation of formulations as well as the technical staff of Joanneum Research for their high-quality performance of OFM and biopsy sampling studies.

Author information

Author notes

  1. Line Hollesen Basse

    Present address: Discovery & Development PKPD, Novo Nordisk A/S, Novo Nordisk Park, 2760, Måløv, Denmark

Authors and Affiliations

  1. LEO Pharma Global Research & Development, Industriparken 55, 2750, Ballerup, Denmark

    Stefan Eirefelt, Malene Bertelsen, Fredrik Johansson, Jens Larsen, Simon Feldbæk Nielsen & Maja Lambert

  2. Joanneum Research Forschungsgesellschaft mbH, Health–Institute for Biomedicine and Health Sciences, Neue Stiftingtalstraße 2, 8010, Graz, Austria

    Joanna Hummer, Thomas Birngruber & Frank Sinner

Authors
  1. Stefan Eirefelt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joanna Hummer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Line Hollesen Basse
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Malene Bertelsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fredrik Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Thomas Birngruber
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Frank Sinner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jens Larsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Simon Feldbæk Nielsen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maja Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maja Lambert.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Eirefelt, S., Hummer, J., Basse, L.H. et al. Evaluating Dermal Pharmacokinetics and Pharmacodymanic Effect of Soft Topical PDE4 Inhibitors: Open Flow Microperfusion and Skin Biopsies. Pharm Res 37, 243 (2020). https://doi.org/10.1007/s11095-020-02962-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-020-02962-1

Key words

Search

Navigation