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Research Article

Cancer Research Frontiers. 2016 Sept; 2(3): 330-351. doi: 10.17980/2016.330

Clinical pharmacology profile of an oral selective androgen receptor down-regulator, AZD3514: Implications on the design of ongoing castrate-resistant prostate cancer clinical studies

Angela W. Dymond1, Marc-Antoine Fabre1, Gareth D. James2, Masako Hirata3, Simon A. Smith4, Paul A. Dickinson1,5, Michael Dymond6, Glen Clack7

 

1Quantitative Clinical Pharmacology, Early Clinical Development, AstraZeneca, Alderley Park, Macclesfield, UK

2 PHASTAR, Unit 2, 2a Bollo Lane, London W4 5LE, UK

3Clinical Science Division, Research and Development, AstraZeneca K.K., Osaka, Japan

4Oncology Translational Medicine Unit, AstraZeneca, Melbourn Science Park, Melbourn, Royston, UK

5Current Address, Seda Pharmaceutical Development Services®, The BioHub at Alderley Park, Alderley Edge, UK

6Discovery Sciences Statistics, AstraZeneca, Alderley Park, Cheshire, Macclesfield, UK

 7Oncology Translational Medicine Unit, AstraZeneca, Alderley Park, Macclesfield, UK

 

*Corresponding author: Simon A. Smith, Oncology Translational Medicine Unit, AstraZeneca, Melbourn Science Park, Melbourn, Royston, UK. E-mail: Simon.A.Smith@astrazeneca.com; Telephone: +44 7557 540 988

Citation: Angela Dymond, et al. Clinical pharmacology profile of an oral selective androgen receptor down-regulator, AZD3514: Implications on the design of ongoing castrate-resistant prostate cancer clinical studies. Cancer Research Frontiers. 2016 Sept; 2(3): 330-351. doi: 10.17980/2016.330

Copyright: @ 2016 Angela Dymond, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Competing Interests: All authors were at the time of study conduct employees of AstraZeneca with the exception on Gareth D. James, who received payment from AstraZeneca for services rendered. P. Dickinson owns shares in AstraZeneca and is Director of a company with a contract to provide services to AstraZeneca.

Received June 7, 2016; Revised Aug 17, 2016; Accepted Aug 15, 2016. Published Sept 16, 2016

 

Abstract

Purpose: To describe the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD3514 and how the design of the first-time-in-human study was adapted based on the emerging clinical PK.

Patients and methods: Data were collected from 77 patients with castrate-resistant prostate cancer from two dose-escalation studies, in Europe (NCT01162395) and Japan (NCT01351688). PK parameters were derived from plasma and urine data and exploration of PK-PD relationships were performed. Post hoc analysis was conducted to investigate time-dependent changes and inter- and intra-patient variability in PK.

Results: AZD3514 was rapidly absorbed and plasma levels declined in a bi-phasic manner with no ethnic differences. Plasma exposure to AZD3514 was dose proportional. Generally, overall exposures were similar between visits within each patient, but varied between patients within each cohort. A switch to twice-daily dosing, to increase exposure, produced a marked time-dependent reduction in area under the curve of 30% and an increase in apparent clearance (from 17 to 25 L/h) at steady state compared to single doses. Emerging study data showed that low baseline testosterone may influence prostate-specific antigen (PSA) reductions by AZD3514. Combination cohorts with abiraterone acetate, a drug that decreases testosterone in CRPC patients, did not result in meaningful decreases in PSA.

Discussion and conclusions: Despite adaptation of the clinical strategy from emerging PK and PD data, the hypothesis around androgen receptor (AR) modulation through AR down-regulation could not be tested due to the time-dependent effect on AZD3514 PK, which prevented coverage above the target concentration. Further testing of this hypothesis is warranted.               

Key words: clinical trial, phase 1, pharmacokinetics, pharmacodynamics, AZD3514, castrate-resistant prostate cancer, adaptive design

 

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