Exposure-response analysis to assess concentration–QTc relationship of CC-122
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 cer...
Guardado en:
| Autores principales: | , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Dove Medical Press
2016
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/93c0b24e1f2a45bea58007173b9899bd |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:93c0b24e1f2a45bea58007173b9899bd |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:93c0b24e1f2a45bea58007173b9899bd2021-12-02T01:06:58ZExposure-response analysis to assess concentration–QTc relationship of CC-1221179-1438https://doaj.org/article/93c0b24e1f2a45bea58007173b9899bd2016-09-01T00:00:00Zhttps://www.dovepress.com/exposure-response-analysis-to-assess-concentrationndashqtc--relationsh-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438Yan 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 effectLi YCarayannopoulos LN,Thomas MPalmisano MZhou SDove Medical PressarticleCC-122cardiovascular assessmentexposure response analysisQT/QTcFQT prolongation effectTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol Volume 8, Pp 117-125 (2016) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
CC-122 cardiovascular assessment exposure response analysis QT/QTcF QT prolongation effect Therapeutics. Pharmacology RM1-950 |
| spellingShingle |
CC-122 cardiovascular assessment exposure response analysis QT/QTcF QT prolongation effect Therapeutics. Pharmacology RM1-950 Li Y Carayannopoulos LN,Thomas M Palmisano M Zhou S Exposure-response analysis to assess concentration–QTc relationship of CC-122 |
| description |
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 |
| format |
article |
| author |
Li Y Carayannopoulos LN,Thomas M Palmisano M Zhou S |
| author_facet |
Li Y Carayannopoulos LN,Thomas M Palmisano M Zhou S |
| author_sort |
Li Y |
| title |
Exposure-response analysis to assess concentration–QTc relationship of CC-122 |
| title_short |
Exposure-response analysis to assess concentration–QTc relationship of CC-122 |
| title_full |
Exposure-response analysis to assess concentration–QTc relationship of CC-122 |
| title_fullStr |
Exposure-response analysis to assess concentration–QTc relationship of CC-122 |
| title_full_unstemmed |
Exposure-response analysis to assess concentration–QTc relationship of CC-122 |
| title_sort |
exposure-response analysis to assess concentration–qtc relationship of cc-122 |
| publisher |
Dove Medical Press |
| publishDate |
2016 |
| url |
https://doaj.org/article/93c0b24e1f2a45bea58007173b9899bd |
| work_keys_str_mv |
AT liy exposureresponseanalysistoassessconcentrationndashqtcrelationshipofcc122 AT carayannopouloslnthomasm exposureresponseanalysistoassessconcentrationndashqtcrelationshipofcc122 AT palmisanom exposureresponseanalysistoassessconcentrationndashqtcrelationshipofcc122 AT zhous exposureresponseanalysistoassessconcentrationndashqtcrelationshipofcc122 |
| _version_ |
1718403333149949952 |