Clinical Pharmacology: Advances and Applications (Sep 2016)
Exposure-response analysis to assess concentration–QTc relationship of CC-122
Abstract
Yan Li, Leonidas N Carayannopoulos, Michael Thomas, Maria Palmisano, Simon Zhou Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ, USA Abstract: CC-122 hydrochloride is a novel pleiotropic pathway modifier compound that binds cereblon, a substrate receptor of the Cullin 4 RING E3 ubiquitin ligase complex. CC-122 has multiple activities including modulation of immune cells, antiproliferative activity of multiple myeloma and lymphoma cells, and antiangiogenic activity. CC-122 is being developed as an oncology treatment for hematologic malignancies and advanced solid tumors. Cardiovascular and vital sign assessments of CC-122 have been conducted in hERG assays in vitro and in a 28-day good laboratory practice monkey study with negative signals. To assess the potential concentration–QTc relationship in humans and to ascertain or exclude a small QT effect by CC-122, a plasma concentration exposure- and ΔQTcF-response model of CC-122 was developed. Intensive CC-122 concentration and paired triplicate electrocardiogram data from a single ascending dose study were included in the analysis. The parameters included in the final linear exposure-response model are intercept, slope, and treatment effect. The slope estimate of 0.0201 with 90% CI of (0.009, 0.035) indicates a weak relationship between ΔQTcF and CC-122 concentration. The upper bounds of the 90% CI of the model-predicted ΔΔQTcF effect at Cmax from the 4 mg clinical dose and the supratherapeutic dose of 15 mg (1.18 ms and 8.76 ms, respectively) are <10 ms threshold, suggesting that the risk of CC-122 QT prolongation effect at the relevant therapeutic dose range from 1 mg to 4 mg is low. Keywords: cardiovascular assessment, QT prolongation effect
