Supplementary Table 1. PBPK model-predicted veliparib plasma pharmacokinetic (PK) parameters and mechanistic kidney model parameters under different scenarios. Supplementary Figure S1. In vitro metabolism of veliparib. The disappearance of veliparib (A) and formation of M8 (B) when veliparib (100 micromol/L) was incubated with recombinant human CYP1A1, 1A2, 2C9, 2C19, 2D6, 3A4, and 3A5 SupersomesTM at CYP concentrations of 10 to 160 pmol/mL. The negative control was the incubation with insect cell control SupersomesTM. The points are the average of duplicate determination (with coefficient variation <10%). Supplementary Figure S2. Goodness-of-fit plots for the final parent-metabolite population pharmacokinetic model. Supplementary Figure S3. Sensitivity analysis showing the impact of ABCB1 activity (intrinsic efflux clearance) on veliparib plasma pharmacokinetic parameters and mechanistic kidney model parameters. Sensitivity analysis was performed with ABCB1 intrinsic efflux clearance varying from 0.1 to 3 microl/min/106 cells while OCT2 intrinsic uptake clearance fixing at 8.59 microl/min/106 cells.
ARTICLE ABSTRACT
Purpose: 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).Experimental Design: 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. Clin Cancer Res; 20(15); 3931–44. ©2014 AACR.
