RT Journal Article
SR Electronic
T1 Whole-Body Physiologically Based Pharmacokinetic Model for Nutlin-3a in Mice after Intravenous and Oral Administration
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 15
OP 21
DO 10.1124/dmd.110.035915
VO 39
IS 1
A1 Fan Zhang
A1 Michael Tagen
A1 Stacy Throm
A1 Jeremy Mallari
A1 Laura Miller
A1 R. Kiplin Guy
A1 Michael A. Dyer
A1 Richard T. Williams
A1 Martine F. Roussel
A1 Katie Nemeth
A1 Fangyi Zhu
A1 Jiakun Zhang
A1 Min Lu
A1 John C. Panetta
A1 Nidal Boulos
A1 Clinton F. Stewart
YR 2011
UL http://dmd.aspetjournals.org/content/39/1/15.abstract
AB Nutlin-3a is an MDM2 inhibitor that is under investigation in preclinical models for a variety of pediatric malignancies, including retinoblastoma, rhabdomyosarcoma, neuroblastoma, and leukemia. We used physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of nutlin-3a in the mouse. Plasma protein binding and blood partitioning were assessed by in vitro studies. After intravenous (10 and 20 mg/kg) and oral (50, 100, and 200 mg/kg) dosing, tissue concentrations of nutlin-3a were determined in plasma, liver, spleen, intestine, muscle, lung, adipose, bone marrow, adrenal gland, brain, retina, and vitreous fluid. The PBPK model was simultaneously fit to all pharmacokinetic data using NONMEM. Nutlin-3a exhibited nonlinear binding to murine plasma proteins, with the unbound fraction ranging from 0.7 to 11.8%. Nutlin-3a disposition was characterized by rapid absorption with peak plasma concentrations at approximately 2 h and biphasic elimination consistent with a saturable clearance process. The final PBPK model successfully described the plasma and tissue disposition of nutlin-3a. Simulations suggested high bioavailability, rapid attainment of steady state, and little accumulation when administered once or twice daily at dosages up to 400 mg/kg. The final model was used to perform simulations of unbound tissue concentrations to determine which dosing regimens are appropriate for preclinical models of several pediatric malignancies.