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Lookup NU author(s): Professor Nicola CurtinORCiD
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Purpose: Rucaparib is a potent Poly (ADP-ribose) Polymerase (PARP) inhibitor currently under clinical development. The objectives of this analysis were to establish population PK and PK/PD models for rucaparib, and to evaluate the predictability of PARP activity in PBL for PARP activity in tumor tissues.Experimental Design: Rucaparib concentrations and PARP activity in human PBLs and tumor issues were obtained from 32 patients with solid tumors in a Phase 1 First-in-Patient study. Simulations were conducted to evaluate different dosing regimens.Results: A 3-compartment PK model best described the PK of rucaparib. An Emax model best described the exposure and PARP inhibition relationship. The maximum PARP inhibition (Imax) achieved in PBLs and in tumors were 90.9% and 90.0% of the baseline PARP activity, and the IC50 values were 1.05 ng/mL and 1.10 ng/mL, respectively. PAR polymer baseline value was found to be a covariate of Emin.Conclusion: Population PK and PK/PD models have been established to describe population PK of rucaparib and the relationship between rucaparib plasma concentration and PARP inhibition in both PBLs and tumor issues. Results from this trial indicated that PARP inhibition in PBLs can be used as a substitute for PARP inhibition in melanoma tumor tissues.
Author(s): Wang DD, Li CZ, Sun W, Zhang SZ, Shalinsky DR, Kern KA, Curtin NJ, Sam WJ, Kirkpatrick TR, Plummer R
Publication type: Article
Publication status: Published
Journal: Clinical Pharmacology in Drug Development
Year: 2015
Volume: 4
Issue: 2
Pages: 89-98
Print publication date: 01/03/2015
Online publication date: 26/01/2015
Acceptance date: 04/11/2014
ISSN (print): 2160-763X
ISSN (electronic): 2160-7648
Publisher: Wiley-Blackwell Publishing Ltd.
URL: http://dx.doi.org/10.1002/cpdd.176
DOI: 10.1002/cpdd.176
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