Approach to Evaluating QT Prolongation of Quetiapine Fumarate in Late Stage of Clinical Development Using Concentration-QTc Modeling and Simulation in Japanese Patients With Bipolar Disorder

Purpose: Quetiapine has been reported to prolong the QT interval, and has been used as a positive control in thorough QT studies. The objective of the present study was to evaluate, in the late stages of clinical development, the QT-prolongation effects of the extended-release (XR) formulation of quetiapine at the approved dose in Japanese patients with bipolar disorder, using concentration-QT modeling and simulation.Methods: Plasma concentrations of quetiapine and 4 of its metabolites (M1, M2, M4, and M5), and the QT interval corrected using the Fridericia formula (QTcF), were used for the concentration-QT analysis. Data from intensive electrocardiogram monitoring at predose and at 4, 6, 10, and 24 h after the administration of the last dose were pooled from a Phase I trial (6949-CL-0006) and from sparse sampling in late-stage clinical trials (6949-CL-0005, -0021, -0022, and -0023) in Japanese patients (N = 505). The upper limit of 1-sided 95% confidence interval (CI) of the changes from baseline in QTcF (Delta QTcF) at the geometric mean Cmax of a therapeutic dose of 300 mg once daily was predicted using a linear mixed-effects model, with the intercept as a random effect specifying a subject effect.Findings: For quetiapine and M2, but not M1, M4, or M5, positive slopes were observed between Delta QTcF and concentration. The predicted upper limits of the 1-sided 95% CIs did not exceed the regulatory threshold of 10 msec. Therefore, QTc prolongation is unlikely to be clinically relevant at the approved dose of quetiapine XR. (C) 2020 Published by Elsevier Inc.