Clinical and Model-Based Evaluation of the Effect of Glasdegib on Cardiac Repolarization From a Randomized Thorough
Joanna C Masters1, Naveed Shaik1, Laure Mendes da Costa2
1Pfizer Inc., San Diego, California, USA.
Insights
Glasdegib, a Hedgehog pathway inhibitor, was evaluated for its effect on the QTc interval in a thorough QT study. Results showed therapeutic and supratherapeutic doses did not significantly prolong the QTc interval, indicating cardiac safety.
Area of Science:
- Pharmacology
- Cardiology
- Oncology
Background:
- Glasdegib is a selective oral inhibitor of the Hedgehog signaling pathway.
- Cardiovascular safety, specifically QT interval prolongation, is a critical consideration for oncology drugs.
Purpose of the Study:
- To evaluate the effect of glasdegib on the QTc interval using a thorough QT study design.
- To assess the cardiac safety profile of glasdegib at therapeutic and supratherapeutic doses.
Main Methods:
- A phase 1, double-blind, thorough QT study (NCT03162900) enrolled 36 healthy volunteers.
- Participants received single doses of glasdegib (150 mg and 300 mg), moxifloxacin (positive control), or placebo under fasted conditions.
- QTc interval was assessed using QT interval corrected using Fridericia's formula (QTcF).
Main Results:
- Glasdegib, at both therapeutic and supratherapeutic doses, demonstrated no significant effect on the QTc interval.
- The upper bound of the 90% confidence intervals for QTcF differences between glasdegib and placebo was below the 20-millisecond threshold.
- Exposure-response analysis indicated no meaningful effect of glasdegib on heart rate.
Conclusions:
- Glasdegib is considered safe regarding QTc interval prolongation at therapeutic and supratherapeutic doses.
- The findings support the cardiac safety of glasdegib in oncology patients.
- No clinically significant effect on QTc interval or heart rate was observed.
Abstract:
Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double-blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions. The study demonstrated that therapeutic and supratherapeutic doses of glasdegib had no significant effect on QTc interval; the upper bound of the 2-sided 90% confidence intervals (CIs) for all time-matched least-squares mean differences in QT interval corrected using Fridericia's formula (QTcF) between glasdegib and placebo was below the prespecified criterion of 20 milliseconds (Food and Drug Administration correspondence reviewed and accepted). Based on an exposure-response analysis, glasdegib was determined not to have a meaningful effect on heart rate (change in RR interval). The mean (90%CI) model-derived baseline and placebo-adjusted QTcF at the average maximum observed concentration values corresponding to therapeutic and supratherapeutic glasdegib doses was 7.3 milliseconds (6.5-8.2 milliseconds) and 13.7 milliseconds (12.0-15.5 milliseconds), respectively. Together these results demonstrated that following therapeutic and supratherapeutic glasdegib dosing, the change in QTc from baseline was well below the 20-millisecond threshold of clinical concern in oncology.
