Yiming Cheng1, Jian Chen2, Michael Pourdehnad3, Simon Zhou1, Yan Li1. 1. Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, Summit, NJ, USA. 2. Non-Clinical Research & Development, Bristol Myers Squibb, Summit, NJ, USA. 3. Early Clinical Development, Bristol Myers Squibb, San Francisco, CA, USA.
Abstract
BACKGROUND: CC-122 is a cereblon-modulating agent that exerts direct cell-autonomous activity against malignant B cells and immunomodulatory effects. Herein, a population pharmacokinetic (popPK) model of CC-122 was developed and the influence of demographic and disease-related covariates on population pharmacokinetic parameters was assessed based on data from three clinical studies of CC-122 (dose range, 0.5-15 mg) in healthy subjects and cancer patients. METHODS: Nonlinear mixed effects modeling was employed in developing a population pharmacokinetic model of CC-122 based on 298 patients from 3 clinical studies. RESULTS: The PK of CC-122 was adequately described with a two-compartment model with first-order absorption and elimination. Tumor types were found to be significantly correlated with apparent clearance (CL/F) and apparent volume of distribution of the central compartment. Creatinine clearance was identified as a statistically significant covariate of CL/F. Sex and body weight were statistically but not clinically relevant on V2/F. CONCLUSION: In conclusion, the two-compartment model built can be used to adequately describe the time course of the population pharmacokinetics of CC-122 and should serve as the basis for dose adjustment decision-making of CC-122.
BACKGROUND: CC-122 is a cereblon-modulating agent that exerts direct cell-autonomous activity against malignant B cells and immunomodulatory effects. Herein, a population pharmacokinetic (popPK) model of CC-122 was developed and the influence of demographic and disease-related covariates on population pharmacokinetic parameters was assessed based on data from three clinical studies of CC-122 (dose range, 0.5-15 mg) in healthy subjects and cancer patients. METHODS: Nonlinear mixed effects modeling was employed in developing a population pharmacokinetic model of CC-122 based on 298 patients from 3 clinical studies. RESULTS: The PK of CC-122 was adequately described with a two-compartment model with first-order absorption and elimination. Tumor types were found to be significantly correlated with apparent clearance (CL/F) and apparent volume of distribution of the central compartment. Creatinine clearance was identified as a statistically significant covariate of CL/F. Sex and body weight were statistically but not clinically relevant on V2/F. CONCLUSION: In conclusion, the two-compartment model built can be used to adequately describe the time course of the population pharmacokinetics of CC-122 and should serve as the basis for dose adjustment decision-making of CC-122.
Authors: Yan Li; Kimberly MacGorman; Liangang Liu; Jian Chen; Matthew Hoffmann; Maria Palmisano; Simon Zhou Journal: Clin Pharmacol Drug Dev Date: 2019-12-31
Authors: Drew W Rasco; Kyriakos P Papadopoulos; Michael Pourdehnad; Anita K Gandhi; Patrick R Hagner; Yan Li; Xin Wei; Rajesh Chopra; Kristen Hege; Jorge DiMartino; Kent Shih Journal: Clin Cancer Res Date: 2018-09-10 Impact factor: 12.531
Authors: Roberto A Abbiati; Michael Pourdehnad; Soraya Carrancio; Daniel W Pierce; Shailaja Kasibhatla; Mark McConnell; Matthew W B Trotter; Remco Loos; Cristina C Santini; Alexander V Ratushny Journal: AAPS J Date: 2021-08-27 Impact factor: 4.009