Preclinical Pharmacokinetics of MI-219, a Novel Human Double Minute 2 (HDM2) Inhibitor and Prediction of Human Pharmacokinetics

Abstract

-Purpose. The two purposes of this study were evaluating preclinical pharmacokinetics of MI-219 and predicting clearance (CL) and volume of distribution at steady-state (Vd ss ) of MI-219 in humans. Methods. 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 f u 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 Vd ss (Wajima's method). In addition, simultaneous interspecies scaling of CL, Vd ss and concentration-time profile were performed by using Nonlinear Mixed Effects Modeling (NONMEM). Results. Preclinical studies showed that the elimination of MI-219 was mainly through metabolism. The validation using observed monkey CL and Vd ss showed that MA, IVIVE and Oie-Tozer methods were accurately than the other methods. Human CL of MI-219 predicted by ME and IVIVE was between 0.237-0.342 L*h -1 *kg -1. Human Vd ss predicted by Oie-Tozer method and allometric scaling of unbound volume of distribution of tissues (V T /fu T ) method was between 0.93-1.40 L*kg -1 . Superimposition of rat, monkey and dog data was observed in Dedrick plots and Wajima's transformations. Conclusions. The predicted human pharmacokinetics is useful for the design of first-in-human study.

p53 Family and Cellular Stress Responses in Cancer

“…MI-219 has been shown to activate p53-dependent pathways, which initiated cell-cycle arrest and apoptosis in a number of cancer cell lines, whereas primary cells remained unaffected by these p53-mediated effects ( 199 ). In a preclinical trial, the pharmacological properties of MI-219 were tested and dosages were predicted for use in phase I clinical studies ( 201 ).…”

p53–MDM2 and MDMX Antagonists

“…16,32-34 A more advanced compound (20, K i ¼ 0.44 nM) demonstrated improved oral bioavailability in rats and succeeded in two xenograft models imparting complete tumor regression 35. Optimization of the primary scaffold produced compounds with K i values in the low μM and nM range (18-20), giving promising results in in vitro and in vivo assays with compounds 18 and 19 showing K i values of 8.5 μM and 5 nM, respectively.…”

In Vitro and In Vivo Pharmacokinetics of Aminoalkylated Diarylpropanes NP085 and NP102

“…The CL int in the incubations was expressed as microliters/minute/milligram (microsomes) and was scaled to the apparent clearance for the whole liver (whole-liver CL int ). The following scaling factors were used for the microsomal protein yield per gram of liver (MPGL): human, 52.5 mg/g (13); mouse, 87.5 mg/g (14).…”