Journal Article

Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration-resistant prostate cancer

Chi, K. N., Molina, A., Pankras, C., Pili, R., Acharya, M., Tolcher, A. W., Kheoh, T., Gonzalez, M., Trinh, A., Shore, N. D., Jiao, J. J., Tran, N.

2012

Overview

Purpose Abiraterone is the active metabolite of the pro-drug abiraterone acetate (AA) and a selective inhibitor of CYP17, a key enzyme in testosterone synthesis, and improves overall survival in postdocetaxel metastatic castration-resistant prostate cancer (mCRPC). This open-label, single-arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval. Methods The study was conducted in 33 patients with mCRPC. Patients received AA 1,000 mg orally once daily + prednisone 5 mg orally twice daily. Electrocardiograms (ECGs) were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle 1 Day-1. Serial ECG recordings and time-matched pharmacokinetic (PK) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1. Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8. Results After AA administration, the upper bound of the 2-sided 90 % confidence interval (CI) for the mean baseline-adjusted QTcF change was <10 ms; no patients discontinued due to QTc prolongation or adverse events. No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [estimated slope (90 % CI): 0.0031 (−0.0040, 0.0102)]. Conclusions There is no significant effect of AA plus prednisone on the QT/QTc interval in patients with mCRPC.

• Publisher: Springer-Verlag,Springer,Springer Nature B.V
• Subject: Abiraterone Acetate / Androgens - metabolism / Androstadienes - administration & dosage / Antineoplastic agents / Antineoplastic Combined Chemotherapy Protocols - administration & dosage / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - blood / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Biological and medical sciences / Cancer Research / Drug Administration Schedule / Electrocardiography - drug effects / Gynecology. Andrology. Obstetrics / Heart Rate - drug effects / Humans / Long QT Syndrome - chemically induced / Male / Male genital diseases / Medical sciences / Medicine / Medicine & Public Health / Neoplasms, Hormone-Dependent - blood / Neoplasms, Hormone-Dependent - drug therapy / Neoplasms, Hormone-Dependent - enzymology / Neoplasms, Hormone-Dependent - pathology / Nephrology. Urinary tract diseases / Oncology / Orchiectomy / Original / Original Article / Pharmacology. Drug treatments / Pharmacology/Toxicology / Prednisone - administration & dosage / Prostatic Neoplasms - blood / Prostatic Neoplasms - drug therapy / Prostatic Neoplasms - enzymology / Prostatic Neoplasms - pathology / Steroid 17-alpha-Hydroxylase - antagonists & inhibitors / Tumors / Tumors of the urinary system / Urinary tract. Prostate gland