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Exposure-response analysis to assess the concentration-QTc relationship of CC-122

Yan Li1, Leonidas N Carayannopoulos1, Michael Thomas1

  • 1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA.

Clinical Pharmacology : Advances and Applications
|September 28, 2016
PubMed

Insights

CC-122 hydrochloride, a novel cancer therapy, shows a low risk of QT prolongation in humans. This pathway modifier demonstrated a weak concentration-QTc relationship, staying below the 10 ms threshold at therapeutic doses.

Area of Science:

  • Pharmacology
  • Oncology
  • Cardiovascular Safety

Background:

  • CC-122 hydrochloride is a novel pleiotropic pathway modifier targeting the cereblon E3 ubiquitin ligase complex.
  • It exhibits immunomodulatory, antiproliferative, and antiangiogenic activities, positioning it as a potential oncology treatment for hematologic malignancies and solid tumors.

Purpose of the Study:

  • To assess the potential concentration-QTc relationship of CC-122 hydrochloride in humans.
  • To determine if CC-122 hydrochloride causes a clinically significant QT interval prolongation.

Main Methods:

  • Development of a plasma concentration exposure- and ΔQTcF-response model using data from a single ascending dose study.
  • Analysis included intensive CC-122 concentration and paired triplicate electrocardiogram data.
  • A linear exposure-response model was employed to estimate the relationship between CC-122 concentration and QTcF changes.

Main Results:

  • The slope estimate of 0.0201 (90% CI: 0.009, 0.035) indicated a weak relationship between ΔQTcF and CC-122 concentration.
  • Model-predicted ΔΔQTcF effects at Cmax for 4 mg and 15 mg doses were 1.18 ms and 8.76 ms, respectively.
  • These predicted effects remained below the <10 ms threshold.

Conclusions:

  • The risk of CC-122 hydrochloride-induced QT prolongation is low at the relevant therapeutic dose range (1 mg to 4 mg).
  • The study provides evidence supporting the cardiovascular safety profile of CC-122 hydrochloride concerning QT interval prolongation.
Keywords:
QT prolongation effectcardiovascular assessment

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