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PARP activity in peripheral blood lymphocytes as a predictive biomarker for PARP inhibition in tumor tissues – A population pharmacokinetic/pharmacodynamic analysis of rucaparib
Author(s) -
Wang Diane D.,
Li Chunze,
Sun Wan,
Zhang Shuzhong,
Shalinsky David R.,
Kern Kenneth A.,
Curtin Nicola J.,
Sam WaiJohnn,
Kirkpatrick Tanya R.,
Plummer Ruth
Publication year - 2015
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.176
Subject(s) - medicine , pharmacodynamics , biomarker , pharmacokinetics , poly adp ribose polymerase , peripheral blood , pharmacology , population , parp inhibitor , oncology , biochemistry , environmental health , polymerase , gene , chemistry
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 IC 50 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.