Abstract 3889: Population pharmacokinetic/pharmacodynamic evaluation of the effect of glasdegib exposure on cardiac repolarization (QT interval) in cancer patients
Authors: Fostvedt Luke , Shaik Naveed , Martinelli Giovanni , Wagner Andrew , Ruiz-Garcia Ana 
Published: August 2019

Glasdegib inhibits Hedgehog signaling through Smoothened. Glasdegib (100 mg once daily [QD]) is in clinical development as a first-line treatment for adults with acute myeloid leukemia (AML). In two dose-escalation studies, involving cancer patients with either hematologic malignancies or advanced solid tumors, instances of QT interval prolongation occurred at high dose levels. The current analysis characterizes the exposure-response (E-R) relationship between the mean heart rate corrected QT interval (QTc) and glasdegib plasma concentration using data from these two studies. The glasdegib single-agent, dose-escalation studies collected pharmacokinetic (PK) and triplicate electrocardiogram (ECG) pair measurements in patients (n=70) treated over a wide dose range (5-640 mg QD). Fridericia, Bazetts, and population-specific correction factors were examined to determine which correction factor would generate QTc values independent of the underlying heart rate. Linear mixed effects modeling was used to characterize the exposure-response (E-R) relationship between glasdegib plasma concentration and the QTc interval. Potential covariates that may be sources of variability in this E-R relationship (ie, gender, age, and study) were evaluated using a stepwise covariate modeling approach. A parametric bootstrap was performed to estimate the mean QTc change from baseline at the expected mean maximum steady-state plasma concentration (Cmax) at the 100 mg QD therapeutic dose, as well as at the supratherapeutic Cmax (a mean 40% increase observed in the presence of a strong CYP3A inhibitor with the most extreme observed individual increase of 100%). The magnitude of the QTcF change was characterized using a 95% confidence interval at the Cmax concentrations of interest. Glasdegib did not directly affect heart rate. The Fridericia and population-specific correction factors were adequate in removing the heart rate dependence of the QT interval. Based on the model, a positive relationship was established between glasdegib plasma concentration and the QTcF interval. None of the demographic characteristics explored as potential covariates had a statistically significant impact on the E-R relationship. The predicted ΔQTcF mean (upper bound of 95% CI) from baseline at the therapeutic Cmax was 5.30 (6.54) msec. At supratherapeutic concentrations (40% increase and 100% increases over therapeutic Cmax) the change from baseline was 7.42 (8.74) msec and 12.09 (14.25) msec, respectively. The potential for glasdegib exposure to affect the QTc interval was well characterized in this PK/PD analysis. The upper bound (95% CI) of the model predicted ΔQTc from baseline at the therapeutic and supratherapeutic exposures fell below the 20 msec threshold of clinical concern for oncology drugs. A subsequent Thorough QT study confirmed the findings of this analysis.

Citation Format: Luke Fostvedt, Naveed Shaik, Giovanni Martinelli, Andrew Wagner, Ana Ruiz-Garcia. Population pharmacokinetic/pharmacodynamic evaluation of the effect of glasdegib exposure on cardiac repolarization (QT interval) in cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3889.