Systems Pharmacology Modeling of Prostate-Specific Antigen in Patients With Prostate Cancer Treated With an Androgen Receptor Antagonist and Down-Regulator.
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.
Manchester Pharmacy School, The University of Manchester, UK.
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HB
Mistry
Quantitiative Clinical Pharmacology, AstraZeneca, Alderley Park, UK.
M-A
MA
Fabre
Goosebrook Associates Ltd, The BioHub at Alderley Park Alderley Edge, UK.
J
J
Young
Early Clinical Development, AstraZeneca, Alderley Park, UK.
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G
Clack
Seda Pharmaceutical Development Services, The BioHub at Alderley Park Alderley Edge, UK.
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PA
Dickinson
D059002:Androgen Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008297:Male; D008954:Models, Biological; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors / Q000097:blood*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood* / Q000188:drug therapy*; D011724:Pyridazines / Q000494:pharmacology / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000378:metabolism; D013597:Systems Analysis; D016896:Treatment Outcome
C410798:AR protein, human; C583656:AZD3514; D059002:Androgen Receptor Antagonists; D011724:Pyridazines; D011944:Receptors, Androgen; D017430:Prostate-Specific Antigen