Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure–response analysis

• Published in: Cancer chemotherapy and pharmacology 2016-10, Vol.78 (4), p.847-853
• Main Authors: Freise, Kevin J., Dunbar, Martin, Jones, Aksana K., Hoffman, David, Enschede, Sari L. Heitner, Wong, Shekman, Salem, Ahmed Hamed
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer Research; Dose-Response Relationship, Drug; Electrocardiography - drug effects; Female; Heart Rate - drug effects; Hematologic Neoplasms - complications; Hematologic Neoplasms - drug therapy; Humans; Long QT Syndrome - chemically induced; Long QT Syndrome - epidemiology; Male; Medicine; Medicine & Public Health; Middle Aged; Oncology; Original Article; Pharmacology/Toxicology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - therapeutic use
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-016-3144-1

Purpose Venetoclax (ABT-199/GDC-0199) is a selective first-in-class B cell lymphoma-2 inhibitor being developed for the treatment of hematological malignancies. The aim of this study was to determine the potential of venetoclax to prolong the corrected QT (QT c ) interval and to evaluate the relationship between systemic venetoclax concentration and QT c interval. Methods The study population included 176 male and female patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma ( n  = 105) or non-Hodgkin’s lymphoma ( n  = 71) enrolled in a phase 1 safety, pharmacokinetic, and efficacy study. Electrocardiograms were collected in triplicate at time-matched points (2, 4, 6, and 8 h) prior to the first venetoclax administration and after repeated venetoclax administration to achieve steady state conditions. Venetoclax doses ranged from 100 to 1200 mg daily. Plasma venetoclax samples were collected after steady state electrocardiogram measurements. Results The mean and upper bound of the 2-sided 90 % confidence interval (CI) QT c change from baseline were  60 ms. The effect of venetoclax concentration on both ΔQT c and QT c was not statistically significant ( P  > 0.05). At the mean maximum concentrations achieved with therapeutic (400 mg) and supra-therapeutic (1200 mg) venetoclax doses, the estimated drug effects on QT c were 0.137 (90 % CI [−1.01 to 1.28]) and 0.263 (90 % CI [–1.92 to 2.45]) ms, respectively. Conclusion Venetoclax does not prolong QT c interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QT c interval.