title: Integrated nonclinical and clinical risk assessment of the investigational proteasome inhibitor ixazomib on the QTc interval in cancer patients.
abstract: BACKGROUND
  Ixazomib is the first oral, proteasome inhibitor to reach phase III trials. Here, we present an integrated nonclinical and clinical assessment of ixazomib's effect on QTc intervals.
  
  
  METHODS
  Nonclinical studies assessed (1) the in vitro binding of ixazomib to the hERG channel and (2) its effect on QT/QTc in dogs (N = 4) via telemetry. Pharmacokinetic-matched triplicate electrocardiograms were collected in four clinical phase I studies of intravenous (0.125-3.11 mg/m(2), N = 125, solid tumors/lymphoma) or oral (0.24-3.95 mg/m(2), N = 120, multiple myeloma) ixazomib. The relationship between ixazomib plasma concentration and heart rate (HR)-corrected QT using Fridericia (QTcF) or population (QTcP) methods was analyzed using linear mixed-effects models with fixed effects for day and time.
  
  
  RESULTS
  In vitro binding potency for ixazomib to the hERG channel was weak (K i 24.9 μM; IC50 59.6 μM), and nonclinical telemetry studies showed no QT/QTc prolongation at doses up to 4.2 mg/m(2). In cancer patients, ixazomib, when evaluated at doses yielding various plasma concentrations (with 26 % of data greater than mean C max for the 4 mg phase 3 dose), had no meaningful effect on QTc based on model-predicted mean change in QTcF/QTcP from baseline. There was no relationship between ixazomib concentration and RR, suggesting no effect on HR.
  
  
  CONCLUSIONS
  Ixazomib has no clinically meaningful effects on QTc or HR. Integrating preclinical data and concentration-QTc modeling of phase 1 data may obviate the need for a dedicated QTc study in oncology. A framework for QT assessment in oncology drug development is proposed.
authors.affiliation: Millennium Pharmaceuticals, Inc., a Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, Neeraj.Gupta@takeda.com.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Gupta
authors.forename: Yeamin
authors.initials: Y
authors.lastname: Huh
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hutmacher
authors.forename: Sean
authors.initials: S
authors.lastname: Ottinger
authors.forename: Ai-Min
authors.initials: AM
authors.lastname: Hui
authors.forename: Karthik
authors.initials: K
authors.lastname: Venkatakrishnan
mesh_terms: D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D017321:Clinical Trials, Phase I as Topic; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D061988:Proteasome Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D018570:Risk Assessment
chemical_list: D001896:Boron Compounds; D051638:Ether-A-Go-Go Potassium Channels; D061988:Proteasome Inhibitors; C548400:ixazomib; D005998:Glycine