The QTc modeling we performed for glasdegib was published in the Expert Review of Clinical Pharmacology.

Link to this article: https://doi.org/10.1080/17512433.2021.1925538

Citation: Luke K. Fostvedt, Naveed Shaik, Giovanni Martinelli, Andrew J. Wagner
& Ana Ruiz-Garcia (2021) Exposure–response modeling of the effect of glasdegib on cardiac
repolarization in patients with cancer, Expert Review of Clinical Pharmacology, 14:7, 927-935, DOI:
10.1080/17512433.2021.1925538

ABSTRACT
Purpose: To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with
advanced cancer.
Methods: A concentration–QTc model was developed using data from two glasdegib single-agent,
dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired
with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from
baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in
a supratherapeutic setting.
Results: Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval,
described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia’s formula) as the dependent
variable with glasdegib plasma concentrations from doses of 5–640 mg QD. The predicted mean QTcF
change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at
supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74)
and 12.09 (14.25) msec, respectively.
Conclusions: The relationship of glasdegib exposure and QTc was well characterized by the model. The
effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology
drug.
Trial registration: ClinicalTrials.gov ID: NCT01286467 and NCT00953758.