Cancer Chemotherapy and Pharmacology

, Volume 60, Issue 4, pp 479–488 | Cite as

A phase I pharmacodynamic study of the effects of the cyclin-dependent kinase-inhibitor AZD5438 on cell cycle markers within the buccal mucosa, plucked scalp hairs and peripheral blood mononucleocytes of healthy male volunteers

  • D. Ross Camidge
  • Mike Pemberton
  • Jim Growcott
  • Dereck Amakye
  • David Wilson
  • Helen Swaisland
  • Cheryl Forder
  • Robert Wilkinson
  • Kate Byth
  • Andrew Hughes
Original Article

Abstract

Purpose

AZD5438 is a novel, orally bioavailable, cyclin-dependent kinase (CDK) inhibitor demonstrating preclinical pharmacodynamic (PD) effects on CDK substrates and active growth inhibition of human tumour xenografts. Clinical pharmacokinetic (PK) data shows its plasma t1/2 to be 1–3 h. The main purpose of the current study was to evaluate PD activity of single oral doses of AZD5438 in healthy volunteers. Twelve healthy male subjects received 10, 40 or 60 mg AZD5438 or placebo in a rotating placebo crossover study design. Rapidly proliferating normal tissues [buccal mucosa, peripheral blood mononucleocytes (PBMCs) and plucked scalp hair] were sampled pre-dosing, 1.5 h (tmax), ±6 h post-dosing. The primary PD endpoint, phospho-retinoblastoma protein (pRb) levels in buccal biopsies (unit length labelling index) assessed by immunohistochemistry, was used as a biomarker of CDK activity.

Results

Phospho-pRb levels were demonstrated to decrease in an epitope, dose- and time-dependent manner. Statistically significant reductions in the ratio phospho-pRb/total pRb were detected at 1.5 h post-dose compared to placebo for both 40 mg [S807–S811 epitope geometric least-squares mean (glsmean) ratio = 0.75, P = 0.014] and 60 mg AZD5438 (S807–S811 epitope glsmean ratio = 0.74, P = 0.011; T821 epitope glsmean ratio = 0.72, P = 0.031). No statistically significant differences were noted at 6 h post-dosing, indicating a close PK–PD relationship between AZD5438 and target inhibition. No effects attributable to AZD5438 were detectable on phospho-p27, p27, Ki67 in the buccal mucosa; or on phospho-pRb (S249–T252 epitope), phospho-p27 or Ki67 in the sheath cells of plucked scalp hair, raising issues about the appropriateness of different detection methods/tissues for use as PD biomarkers. In ex vivo stimulated PBMCs, statistically and near-statistically significant anti-proliferative effects, with the suggestion of a dose–response effect, were noted on the incorporation of [3H]-thymidine (stimulated/non-stimulated) at 10, 40 and 60 mg, compared to placebo, at 1.5 h post-dosing (glsmean ratio = 0.65, P = 0.019; 0.70, P = 0.056; 0.51, P = 0.001, respectively).

Conclusions

The modest PD effect, short plasma t1/2 and close PK–PD relationship suggest that multiple daily dosing or sustained release formulations at higher doses will be necessary for AZD5438 to achieve sustained inhibition of CDK in human cancers.

Keywords

Cell cycle AZD5438 CDK Pharmacodynamic Buccal mucosa 

Abbreviations

CPU

Clinical pharmacology unit

UK

United Kingdom

mg

Milligram

kg

Kilogram

ml

Millilitre

DLT

Dose-limiting toxicity

SMC

Safety monitoring committee

MWTD

Maximum well-tolerated dose

PBMC

Peripheral blood mononucleocyte

Cpm

Counts per minute

ANCOVA

Analysis of covariance

glsmean

Geometric least-squares mean

CI

95% Confidence intervals

CV

Coefficient of variance

ULN

Upper limit of normal

t1/2

Half-life

Notes

Acknowledgments

With thanks to Sally Ward, John Freeman and Anita Lindsay (Study Team Management, AstraZeneca, Alderley Park), Graham Bigley, Debbie Oaks and Helen Wombewell (Discovery Medicine Histopathology Group, AstraZeneca, Alderley Park). There are no conflicts of interest for any of the authors.

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • D. Ross Camidge
    • 1
    • 6
  • Mike Pemberton
    • 2
  • Jim Growcott
    • 3
  • Dereck Amakye
    • 3
  • David Wilson
    • 4
  • Helen Swaisland
    • 4
  • Cheryl Forder
    • 5
  • Robert Wilkinson
    • 3
  • Kate Byth
    • 3
  • Andrew Hughes
    • 3
  1. 1.Edinburgh Cancer CentreWestern General HospitalEdinburghUK
  2. 2.University Dental Hospital of ManchesterManchesterUK
  3. 3.Discovery MedicineAstraZenecaCheshireUK
  4. 4.Clinical DevelopmentAstraZenecaCheshireUK
  5. 5.Cancer and Infection Research AreaAstraZenecaCheshireUK
  6. 6.Division of Medical OncologyUniversity of Colorado Health Sciences CenterDenverUSA

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