title: Population pharmacokinetics of ABT-767 in BRCA1 or BRCA2 mutation carriers with advanced solid tumors or in subjects with high grade serous ovarian, primary peritoneal or fallopian tube cancer.
abstract: The objective of the manuscript is to describe the development of a population pharmacokinetic model for ABT-767, a potent and orally bioavailable inhibitor of poly (ADP-ribose) polymerase enzyme, and to evaluate the potential influence of patient demographics and baseline covariates on the pharmacokinetics of ABT-767.
  
  
  
  A total of 1809 plasma ABT-767 concentrations from 90 subjects were used for population pharmacokinetic modeling. Covariates screened for influence on pharmacokinetic parameters were body weight, lean body weight, body surface area, albumin, creatinine clearance, serum creatinine, liver function tests, and age. The effect of food on absorption and bioavailability were also evaluated. Model validation was performed using bootstrap analysis and visual predictive check.
  
  
  
  A two-compartment model with firstorder absorption adequately described the pharmacokinetics of ABT-767. The population estimates of apparent clearance from central compartment (CL/F), volume of central compartment (Vc/F), and absorption rate constant (ka) were 7.34 L/h, 25.8 L, 1.45 h-1, respectively. The estimates of interindividual variabilities (%CV) in CL/F, Vc/F, and kawere 40.4, 40.5, and 53.8%, respectively. The kawas influenced by food. Albumin on CL/F was a statistically significant covariate; however, it explained only 8% of the variability in the pharmacokinetics of ABT-767.
  
  
  
  Albumin on CL/F was the only statistically significant baseline covariate affecting ABT-767 pharmacokinetics, but it only explained a fraction of the pharmacokinetic variability. Dosage adjustments based on body size, age, or mild renal impairment are not needed for ABT-767. The developed model will be used to evaluate ABT-767 exposure-response analyses and to perform simulations for different dose and dosing regimens.
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1N Waukegan Road, AP31-3, North Chicago, IL, 60064, USA. rajendar.mittapalli@abbvie.com.
authors.forename: Rajendar K
authors.initials: RK
authors.lastname: Mittapalli
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1N Waukegan Road, AP31-3, North Chicago, IL, 60064, USA.
authors.forename: Silpa
authors.initials: S
authors.lastname: Nuthalapati
authors.affiliation: Oncology Development, Abbvie Inc., North Chicago, IL, USA.
authors.forename: Stacie Peacock
authors.initials: SP
authors.lastname: Shepherd
authors.affiliation: Department of Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1N Waukegan Road, AP31-3, North Chicago, IL, 60064, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Xiong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000418:Albumins / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001835:Body Weight; D005185:Fallopian Tube Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D018565:Food-Drug Interactions; D006579:Heterozygote; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010534:Peritoneal Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000493:pharmacokinetics*; D011153:Population; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: C000620230:ABT-767; D000418:Albumins; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D001549:Benzamides; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013449:Sulfonamides
keywords: ABT-767; BRCA1 or BRCA2; Food effect; PARP; Population pharmacokinetics