title: PARP activity in peripheral blood lymphocytes as a predictive biomarker for PARP inhibition in tumor tissues - A population pharmacokinetic/pharmacodynamic analysis of rucaparib.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: Diane D
authors.initials: DD
authors.lastname: Wang
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: Chunze
authors.initials: C
authors.lastname: Li
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: Wan
authors.initials: W
authors.lastname: Sun
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: Shuzhong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Shalinsky
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Kern
authors.affiliation: Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Curtin
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: Wai-Johnn
authors.initials: WJ
authors.lastname: Sam
authors.affiliation: Pfizer Inc., San Diego, CA, USA.
authors.forename: Tanya R
authors.initials: TR
authors.lastname: Kirkpatrick
authors.affiliation: Northern Institute for Cancer Research, Medical School, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Plummer
mesh_terms: D015415:Biomarkers / Q000097:blood; D003198:Computer Simulation; D004334:Drug Administration Schedule; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008214:Lymphocytes / Q000187:drug effects* / Q000201:enzymology; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011065:Poly(ADP-ribose) Polymerases / Q000097:blood*
chemical_list: D015415:Biomarkers; D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib; D011065:Poly(ADP-ribose) Polymerases
keywords: mixed-effects modeling; biomarker; pharmacokinetics (PK)/pharmacodynamics (PD); poly (ADP-ribose) polymerase (PARP); rucaparib