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

• Published in: Cancer chemotherapy and pharmacology Vol. 79; no. 3; pp. 587 - 594
• Main Authors: Mittapalli, Rajendar K., Nuthalapati, Silpa, Shepherd, Stacie Peacock, Xiong, Hao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2017; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Albumins - metabolism; Benzamides - administration & dosage; Benzamides - pharmacokinetics; Benzamides - therapeutic use; Biological Availability; Body Weight; BRCA1 Protein - genetics; BRCA2 Protein - genetics; Cancer Research; Fallopian Tube Neoplasms - drug therapy; Fallopian Tube Neoplasms - genetics; Female; Food-Drug Interactions; Heterozygote; Humans; Intestinal Absorption; Male; Medicine; Medicine & Public Health; Middle Aged; Models, Biological; Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Oncology; Original Article; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Peritoneal Neoplasms - drug therapy; Peritoneal Neoplasms - genetics; Pharmacology/Toxicology; Poly(ADP-ribose) Polymerase Inhibitors - pharmacokinetics; Population; Sulfonamides - administration & dosage; Sulfonamides - pharmacokinetics; Sulfonamides - therapeutic use; Population pharmacokinetics; PARP; BRCA1 or BRCA2; Food effect; ABT-767
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-017-3262-4

Purpose 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. Methods 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. Results 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 ( V c / F ), and absorption rate constant ( k a ) were 7.34 L/h, 25.8 L, 1.45 h −1 , respectively. The estimates of interindividual variabilities (%CV) in CL/ F, V c / F , and k a were 40.4, 40.5, and 53.8%, respectively. The k a was 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. Conclusions 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.