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Quantifying Risk of Delayed QT Prolongation of Ipatasertib in Preclinical and Clinical Studies in Cancer Patients

  • 0Genentech, South San Francisco, California, USA.
Clinical and Translational Science +

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July 17, 2025

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July 17, 2025

View abstract on PubMed

Summary

This summary is machine-generated.

Ipatasertib, an AKT inhibitor, showed a mild, delayed QTc prolongation in clinical studies. The drug is unlikely to pose a substantial proarrhythmic risk at therapeutic doses.

Area Of Science

  • Cardiology
  • Pharmacology
  • Clinical Trials

Background

  • QTc prolongation is linked to cardiac arrhythmias like torsades de pointes (TdP).
  • Selective serine/threonine kinase (AKT) inhibitors are investigated for cancer therapy.
  • Assessing cardiac safety, specifically QTc interval effects, is crucial for drug development.

Purpose Of The Study

  • To evaluate the QTc interval prolongation potential of ipatasertib, an AKT inhibitor.
  • To assess the preclinical and clinical cardiac safety of ipatasertib.
  • To determine the proarrhythmic risk associated with ipatasertib treatment.

Main Methods

  • Preclinical in vitro studies assessed inhibition of human Ether-à-go-go-Related Gene (hERG) channels.
  • Two clinical studies (PAM4743g and GP42658) evaluated QTc interval changes.
  • Pharmacokinetic parameters, including time to maximum drug exposure (Tmax), were correlated with QTc effects.

Main Results

  • Preclinical studies indicated ipatasertib and its metabolite M1 do not significantly inhibit hERG channels.
  • Clinical studies revealed a mild, delayed QTc prolongation, with peak effect occurring 2-4 hours after Tmax.
  • The mean increase in QTcF was 10.9 ms, with an upper 95% CI of 19.1 ms, suggesting a limited magnitude of effect.

Conclusions

  • Ipatasertib exhibits a delayed, mild QTc prolongation.
  • The observed QTc effect is unlikely to lead to a substantial proarrhythmic risk at the intended therapeutic dose of 400 mg.
  • Further cardiac safety monitoring may be warranted, but ipatasertib appears relatively safe concerning QTc prolongation.

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