Abstract 3889: Population pharmacokinetic/pharmacodynamic evaluation of the effect of glasdegib exposure on cardiac repolarization (QT interval) in cancer patients

Abstract

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 (C max ) at the 100 mg QD therapeutic dose, as well as at the supratherapeutic C max (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 C max 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 C max was 5.30 (6.54) msec. At supratherapeutic concentrations (40% increase and 100% increases over therapeutic C max ) 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.