title: Venetoclax does not prolong the QT interval in patients with hematological malignancies: an exposure-response analysis.
abstract: 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 (QTc) interval and to evaluate the relationship between systemic venetoclax concentration and QTc interval.
  
  
  
  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.
  
  
  
  The mean and upper bound of the 2-sided 90 % confidence interval (CI) QTc change from baseline were <5 and <10 ms, respectively, at all time points and doses (<400, 400, and >400 mg). Three subjects had single QTc values >500 ms and/or ΔQTc > 60 ms. The effect of venetoclax concentration on both ΔQTc and QTc 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 QTc were 0.137 (90 % CI [-1.01 to 1.28]) and 0.263 (90 % CI [-1.92 to 2.45]) ms, respectively.
  
  
  
  Venetoclax does not prolong QTc interval even at supra-therapeutic doses, and there is no relationship between venetoclax concentrations and QTc interval.
authors: Clinical Pharmacology and Pharmacometrics, Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors: Kevin J
authors: KJ
authors: Freise
authors: Clinical Pharmacology and Pharmacometrics, Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors: Martin
authors: M
authors: Dunbar
authors: Clinical Pharmacology and Pharmacometrics, Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors: Aksana K
authors: AK
authors: Jones
authors: Clinical Pharmacology and Pharmacometrics, Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors: David
authors: D
authors: Hoffman
authors: Medical Affairs, Abbvie, 1 North Waukegan Road, North Chicago, 60064, IL, USA.
authors: Sari L Heitner
authors: SL
authors: Enschede
authors: Clinical Pharmacology and Pharmacometrics, Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors: Shekman
authors: S
authors: Wong
authors: Clinical Pharmacology and Pharmacometrics, Abbvie, 1 North Waukegan Road, North Chicago, IL, 60064, USA. ahmed.salem@abbvie.com.|Clinical Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. ahmed.salem@abbvie.com.
authors: Ahmed Hamed
authors: 0000-0002-9261-1583
authors: AH
authors: Salem
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D019337:Hematologic Neoplasms / Q000150:complications* / Q000188:drug therapy; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax
keywords: BCL-2; CLL; Exposure–response; NHL; QT prolongation; Venetoclax