Complex Disease-, Gene-, and Drug-Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics

• Published in: Clinical cancer research Vol. 20; no. 15; pp. 3931 - 3944
• Main Authors: JING LI, SEONGHO KIM, XIANYI SHA, WIEGAND, Richard, JIANMEI WU, LORUSSO, Patricia
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2014
• Subjects: Antineoplastic agents; Benzimidazoles - adverse effects; Benzimidazoles - pharmacokinetics; Biological and medical sciences; Clinical Trials, Phase I as Topic; Cytochrome P-450 CYP2D6 - genetics; Cytochrome P-450 CYP2D6 - metabolism; Drug Interactions; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Genetic Variation - genetics; Humans; Medical sciences; Models, Biological; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Organic Cation Transport Proteins - metabolism; Organic Cation Transporter 2; Pharmacology. Drug treatments; Phenotype; Poly(ADP-ribose) Polymerase Inhibitors; Renal Insufficiency - chemically induced; Renal Insufficiency - genetics; Renal Insufficiency - metabolism; Tissue Distribution; Antineoplastic agent; Renal function; Enzyme; Isozyme; Cytochrome P450; Transcription factor Oct2; Biological activity; Phenotype; Gene; Benzimidazole derivatives; Veliparib; Genetics; Drug interaction; Cytochrome CYP2D6; Pharmacokinetics
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-0791

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). 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. 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. 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.