Skip to main content

Advertisement

SpringerLink
Log in

Factors determining the optimal body site and method for obtaining punch biopsies of human skin as a tissue in which to assess pharmacodynamic and pharmacokinetic endpoints in drug development studies

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

There are potential advantages to detecting pharmacodynamic (PD) and pharmacokinetic (PK) endpoints in a tissue-based compartment such as the skin during the development of molecularly targeted drugs. We explored regional differences between inner arm, inner thigh, lower back and buttocks in 12 healthy male Caucasian volunteers in the tolerability of skin biopsy procedures; the Ki67 proliferation index; the frequency of detecting hair follicles and sweat glands; and the percentage of melanocytes. We also explored the amounts of tissue and protein obtained, and two separate methods of splitting biopsies for processing in mutually exclusive media. Biopsies from all body sites were well tolerated. The subjective ranking order was inner arm > buttocks = back > thigh. There were no statistically significant differences in the Ki67 labelling index (P>0.05). The frequency of detecting sweat glands was the same in all body sites, but the frequency of detecting hair follicles was higher in back and buttock, compared to arm and thigh. The percentage of melanocytes was significantly lower in the buttocks compared to the back and thigh (P<0.05), but not compared to the arm (P=0.07). A 4-mm punch biopsy yielded a mean of 16.8 mg of tissue (range: 9–28 mg) and 160 μg of protein (range: 80–270 μg). In vivo sample splitting, by following a 2-mm punch with a 4-mm overpunch, had a shorter time from devascularisation to immersion into processing medium than ex vivo dissection of a 4-mm sample, which may be of importance to the assessment of labile endpoints. We conclude that multiple punch biopsies of the skin are feasible, with the buttocks representing the studied body site with the optimal balance between tolerability, hair follicle density and melanocyte density for obtaining tissue in which to assess PD and PK endpoints during drug development studies.

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

Similar content being viewed by others

Abbreviations

IHC:

Immunohistochemistry

CPU:

Clinical Pharmacology Unit

EGFR:

Epidermal growth factor receptor

PK:

Pharmacokinetic

PD:

Pharmacodynamic

GCP:

Good clinical practice

ICH:

International conference on harmonisation

mg:

Milligram

μg:

Microgram

rpm:

Revolutions per minute

H & E:

Haematoxylin and eosin

HPLC:

High pressure liquid chromatography

LCMS:

Liquid chromatography mass spectrometry

ELISA:

Enzyme-linked immunosorbent assay

ANOVA:

Analysis of variance

mm:

Millimetre

p:

Probability

mL:

Millilitre

g:

Gram

μL:

Microlitre

NaCl:

Sodium chloride

mM:

Millimolar

CL:

Confidence limit

Glsmean:

Geometric least squares mean

n/a:

Non-applicable

References

  1. Albanell J, Rojo F, Averbuch S, Feyereislova A, Mascaro JM, Herbst R, LoRusso P, Rischin D, Sauleda S, Gee J, Nicholson RI, Baselga J (2002) Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110–124

    Article  PubMed  CAS  Google Scholar 

  2. Alster TS, Tanzi EL (2003) Hypertrophic scars and keloids: etiology and management. Am J Clin Dermatol 4:235–243

    Article  PubMed  Google Scholar 

  3. Baselga J (2003) Skin as a surrogate tissue for pharmacodynamic end points: is it deep enough? Clin Cancer Res 9:2389–2390

    PubMed  Google Scholar 

  4. Del Bino S, Vioux C, Rossio-Pasquier P, Jomard A, Demarchez M, Asselineau D, Bernerd F (2004) Ultraviolet B induces hyperproliferation and modification of epidermal differentiation in normal human skin grafted on to nude mice. Br J Dermatol 150:658–667

    Article  PubMed  CAS  Google Scholar 

  5. Hidalgo M, Messersmith W (2004) Pharmacodynamic studies in drug development. In: Michael C, Perry MC (ed) American society of clinical oncology educational book, Alexandria, VA, pp 160–163. ISSN 1548–8748

  6. Larsson BS (1993) Interaction between chemicals and melanin. Pigment Cell Res 6:127–133

    Article  PubMed  CAS  Google Scholar 

  7. Malik SN, Siu LL, Rowinsky EK, deGraffenreid L, Hammond LA, Rizzo J, Bacus S, Brattain MG, Kreisberg JI, Hidalgo M (2003) Pharmacodynamic evaluation of the epidermal growth factor receptor inhibitor OSI-774 in human epidermis of cancer patients. Clin Cancer Res 9:2478–2486

    PubMed  CAS  Google Scholar 

  8. Mandell JW (2003) Phosphorylation state-specific antibodies. Am J Pathol 163:1687–1698

    PubMed  CAS  Google Scholar 

  9. McKillop D, Raab G, Eidtmann H, Furnival A, Riva A, Forbes J, Mackey J, Spence MP, Koehler M, Slamon D (2004) Intratumoral and plasma concentrations of gefitinib in breast cancer patients: preliminary results from a presurgical investigatory study (BCIRG 103). In: Proceedings of the American Society of Clinical Oncology: abstract 581

  10. Papini R (2004) Management of burn injuries of various depths. Br Med J 329:158–160

    Article  Google Scholar 

  11. Pasyk KA, Thomas SV, Hassett CA, Cherry GW, Faller R (1989) Regional differences in capillary density of the normal human dermis. Plast Reconstr Surg 83:939–945

    Article  PubMed  CAS  Google Scholar 

  12. Salazar R, Tabernero J, Rojo F, Jimenez E, Montaner I, Casado E, Sala G, Tillner J, Malik R, Baselga J (2004) Dose-dependent inhibition of the EGFR and signalling pathways with the anti-EGFR monoclonal antibody (MAb) EMD 72000 administered every three weeks (q3w). A phase I pharmacokinetic/pharmacodynamic (PK/PD) study to define the optimal biological dose (OBD). In: Proceedings of the American Society of Clinical Oncology: abstract 2002

  13. Sambrook J, Fritsch EF, Maniatis T (1989) Molecular cloning: a laboratory manual, 2nd edn. Cold Spring Harbour, New York. ISBN: 0-87969-309-6

  14. Vanhoefer U, Tewes M, Rojo F, Dirsch O, Schleucher N, Rosen O, Tillner J, Kovar A, Braun AH, Trarbach T, Seeber S, Harstrick A, Baselga J (2004) Phase I study of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with advanced solid tumours that express the epidermal growth factor receptor. J Clin Oncol 22:175–184

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Helen Gillard and Gary Coggon (Study Team Management, AstraZeneca, Alderley Park; Dinah Parums (Pathology Disease Area Clinical Expert, Experimental Medicine) and Graham Betton (Pathologist, Safety Assessment); Staff at the AstraZeneca CPU, Alderley Park. There are no conflicts of interest for any of the authors.

Author information

Authors and Affiliations

  1. Edinburgh Cancer Centre, Western General Hospital, Edinburgh, EH4 2XU, UK

    D. R. Camidge

  2. AstraZeneca, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK

    M. J. Davies, P. J. Laud, A. L. Marshall, M. Cockerill, P. D. Smith & A. M. Hughes

Authors
  1. D. R. Camidge
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. J. Davies
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P. J. Laud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. L. Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Cockerill
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. P. D. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. M. Hughes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. D. Smith.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Camidge, D., Davies, M., Laud, P. et al. Factors determining the optimal body site and method for obtaining punch biopsies of human skin as a tissue in which to assess pharmacodynamic and pharmacokinetic endpoints in drug development studies. Cancer Chemother Pharmacol 57, 52–58 (2006). https://doi.org/10.1007/s00280-005-0024-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-005-0024-5

Keywords

Search

Navigation