PMID: 22579006May 15, 2012Paper

Preclinical pharmacokinetics of MI-219, a novel human double minute 2 (HDM2) inhibitor and prediction of human pharmacokinetics

Journal of Pharmacy & Pharmaceutical Sciences : a Publication of the Canadian Society for Pharmaceutical Sciences, Société Canadienne Des Sciences Pharmaceutiques
Peng ZouDuxin Sun

Abstract

The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vdss) of MI-219 in humans. Pharmacokinetic studies were conducted on mice, rats, dogs, and monkeys. Human CL of MI-219 was predicted using allometric scaling (SA), multi-exponential allometric scaling (ME), rule of exponents (RoE), single species scaling, two-term power equation (TTPE), physiologically based in vitro-in vivo extrapolation (IVIVE), and fu corrected intercept method (FCIM). In vitro assays were conducted to determine in vitro intrinsic CL, protein binding, and blood-plasma partition coefficients. To estimate half-life of MI-219, plasma concentration-time profile in humans was predicted using kallynochron and apolysichron time transformation (Dedrick plots) and normalization with MRT and Vdss (Wajima's method). In addition, simultaneous interspecies scaling of CL, Vdss and concentration-time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vdss showed that MA, IVIVE and Oie-Tozer methods were accurate...Continue Reading

Citations

Mar 10, 2016·Antimicrobial Agents and Chemotherapy·Liezl GibhardLubbe Wiesner
Apr 24, 2014·Apoptosis : an International Journal on Programmed Cell Death·Xin YuDarren R Carpizo
Nov 7, 2014·Frontiers in Oncology·Johanna PflaumMartina Müller
Nov 20, 2014·Chemical Biology & Drug Design·Sara Ibrahim Omar, Jack Tuszynski
Mar 4, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Seigo SanohShigeru Ohta

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