Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach

加药 医学 耐受性 药代动力学 药理学 药效学 不利影响
作者
Brian Higgins,Kelli Glenn,Antje‐Christine Walz,Christian Tovar,Zoran Filipovic,Sazzad Hussain,Edmund Lee,Kenneth Kolinsky,Shahid Tannu,Violeta Adames,Rosario Garrido,Michael Linn,Christophe Meille,David Heimbrook,Lyubomir T. Vassilev,Kathryn Packman
出处
期刊:Clinical Cancer Research [American Association for Cancer Research]
卷期号:20 (14): 3742-3752 被引量:57
标识
DOI:10.1158/1078-0432.ccr-14-0460
摘要

Abstract Purpose: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens. Experimental Design: A pharmacokinetic–pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity. This PKPD model was used to investigate the pharmacokinetics of RG7388 linked to the time-course of the antitumor effect in an osteosarcoma xenograft model in mice. These data were used to prospectively predict intermittent and continuous dosing regimens, resulting in tumor stasis in the same model system. Results: RG7388-induced apoptosis was delayed relative to drug exposure with continuous treatment not required. In initial efficacy testing, daily dosing at 30 mg/kg and twice a week dosing at 50 mg/kg of RG7388 were statistically equivalent in our tumor model. In addition, weekly dosing of 50 mg/kg was equivalent to 10 mg/kg given daily. The implementation of modeling and simulation on these data suggested several possible intermittent clinical dosing schedules. Further preclinical analyses confirmed these schedules as viable options. Conclusion: Besides chronic administration, antitumor activity can be achieved with intermittent schedules of RG7388, as predicted through modeling and simulation. These alternative regimens may potentially ameliorate tolerability issues seen with chronic administration of RG7112, while providing clinical benefit. Thus, both weekly (qw) and daily for five days (5 d on/23 off, qd) schedules were selected for RG7388 clinical testing. Clin Cancer Res; 20(14); 3742–52. ©2014 AACR.
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