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



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 t 1/2 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 (t max), ±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.


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).


The modest PD effect, short plasma t 1/2 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.


Cell cycle AZD5438 CDK Pharmacodynamic Buccal mucosa 



Clinical pharmacology unit


United Kingdom








Dose-limiting toxicity


Safety monitoring committee


Maximum well-tolerated dose


Peripheral blood mononucleocyte


Counts per minute


Analysis of covariance


Geometric least-squares mean


95% Confidence intervals


Coefficient of variance


Upper limit of normal





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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