Unified Assessment of QTc and PK Concentration Data in a Thorough QTc Study Using an Index Set, Indexed by Monotonic Order of PK Concentrations

• Activity Number: 353
• Type: Contributed
• Date/Time: Tuesday, August 6, 2013 : 10:30 AM to 12:20 PM
• Sponsor: Biopharmaceutical Section
• Author(s): Anura Abeyratne*+
• Companies: Astellas Pharma Global Development, Inc
• Keywords: ICH E14 ; QTc interval ; Pharmacokinetics ; Mixed-effects ; Monotonic order ; Crossover design

Abstract

A randomized placebo and positive controlled study is used to assess the effect of drug on the QTc interval prolongation. Typical study design is a crossover and QTc measurements are taken at specified time points pre and post dose. Mixed effects model is utilized to assess the baseline corrected QTc change from placebo for therapeutic, supra-therapeutic, and positive control at each time point. Separate analysis is performed to assess the QTC and PK concentration relationship. Here, we propose to combine QTc and PK concentration data based on an index set, indexed by monotonic order of PK concentrations within treatment. The index set is transferred to the QTc measurements on placebo using subject and time as an identity in a crossover study or simply the time as an identity in a parallel group study. Mixed effects model is utilized to assess the baseline corrected QTc change from placebo for therapeutic, supra-therapeutic, and positive control on the index set. Examples of analysis from crossover and parallel studies will be provided. Assay sensitivity and drug QTc effects can then be judged on the highest ordered index set provided no apparent proteresis and hysteresis effects.