Clinical pharmacology profile of an oral selective androgen receptor down-regulator, AZD3514: Implications on the design of ongoing castrateresistant prostate cancer clinical studies
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.
Full Reference: 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
Link to full text: http://cancer-research-frontiers.org/2016-2-330/