title: Complex disease-, gene-, and drug-drug interactions: impacts of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics.
abstract: OBJECTIVE
  Veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, undergoes renal excretion and liver metabolism. This study quantitatively assessed the interactions of veliparib with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment).
  
  
  METHODS
  Veliparib in vitro metabolism was examined in human liver microsomes and recombinant enzymes carrying wild-type CYP2D6 or functional defect variants (CYP2D6*10 and *4). Plasma pharmacokinetics were evaluated in 27 patients with cancer. A parent-metabolite joint population model was developed to characterize veliparib and metabolite (M8) pharmacokinetics and to identify patient factors influencing veliparib disposition. A physiologically based pharmacokinetic model integrated with a mechanistic kidney module was developed to quantitatively predict the individual and combined effects of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics.
  
  
  RESULTS
  In vitro intrinsic clearance of CYP2D6.1 and CYP2D6.10 for veliparib metabolism were 0.055 and 0.017 μL/min/pmol CYP, respectively. Population mean values for veliparib oral clearance and M8 clearance were 13.3 and 8.6 L/h, respectively. Creatinine clearance was identified as the significant covariate on veliparib oral clearance. Moderate renal impairment, CYP2D6 poor metabolizer, and co-administration of OCT2 inhibitor (cimetidine) increased veliparib steady-state exposure by 80%, 20%, and 30%, respectively. These factors collectively led to >2-fold increase in veliparib exposure.
  
  
  CONCLUSIONS
  Renal function (creatinine clearance) is a significant predictor for veliparib exposure in patients with cancer. Although a single factor (i.e., renal impairment, CYP2D6 deficiency, and reduced OCT2 activity) shows a moderate impact, they collectively could result in a significant and potentially clinically relevant increase in veliparib exposure.
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan lijin@karmanos.org.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Seongho
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Xianyi
authors.initials: X
authors.lastname: Sha
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Richard
authors.initials: R
authors.lastname: Wiegand
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Jianmei
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
mesh_terms: D001562:Benzimidazoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D000075102:Organic Cation Transporter 2; D010641:Phenotype; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051437:Renal Insufficiency / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C491013:SLC22A2 protein, human; C521013:veliparib; D019389:Cytochrome P-450 CYP2D6