1. Systems Pharmacology Modeling of Prostate-Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down-Regulator.
- Author
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Mistry HB, Fabre MA, Young J, Clack G, and Dickinson PA
- Subjects
- Androgen Receptor Antagonists pharmacology, Down-Regulation drug effects, Down-Regulation physiology, Humans, Male, Prostate-Specific Antigen antagonists & inhibitors, Pyridazines pharmacology, Pyridazines therapeutic use, Receptors, Androgen metabolism, Treatment Outcome, Androgen Receptor Antagonists therapeutic use, Models, Biological, Prostate-Specific Antigen blood, Prostatic Neoplasms, Castration-Resistant blood, Prostatic Neoplasms, Castration-Resistant drug therapy, Systems Analysis
- Abstract
First-in-human (FIH) studies with AZD3514, a selective androgen receptor (AR) down-regulator, showed decreases of >30% in the prostate-specific antigen (PSA) in some patients. A modeling approach was adopted to understand these observations and define the optimum clinical use hypothesis for AZD3514 for clinical testing. Initial empirical modeling showed that only baseline PSA correlated significantly with this biological response, whereas drug concentration did not. To identify the mechanistic cause of this observation, a mechanism-based model was first developed, which described the effects of AZD3514 on AR protein and PSA mRNA levels in LNCaP cells with and without dihydrotestosterone (DHT). Second, the mechanism-based model was linked to a population pharmacokinetic (PK) model; PSA effects of clinical doses were subsequently simulated under different clinical conditions. This model was used to adjust the design of the ongoing clinical FIH study and direct the backup program., (© 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)
- Published
- 2016
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