2014
DOI: 10.1158/1078-0432.ccr-14-0460
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Preclinical Optimization of MDM2 Antagonist Scheduling for Cancer Treatment by Using a Model-Based Approach

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 schedul… Show more

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Cited by 56 publications
(43 citation statements)
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“…To this end, Higgins et al have proposed a modeling approach for strategic scheduling of MDM2 PPI inhibitors. 16 …”
Section: Discussionmentioning
confidence: 99%
“…To this end, Higgins et al have proposed a modeling approach for strategic scheduling of MDM2 PPI inhibitors. 16 …”
Section: Discussionmentioning
confidence: 99%
“…Human PK was predicted by a PBPK model and linked to the scaled thrombocytopenia model to predict the time‐course of drug‐induced thrombocytopenia in humans . Simulations suggested dosing regimens projected to provide similar anticancer effect based on a semimechanistic PK‐PD model developed to predict tumor growth inhibition in tumor‐bearing xenograft mice . The most favorable dosing regimen that allowed differentiation of antitumor effect from drug‐induced thrombocytopenia was selected and implemented in the FIH trial.…”
Section: Safety Evaluationsmentioning
confidence: 99%
“…Animals were monitored 2–3 times weekly and euthanized humanely just before showing signs of illness/suffering such as abdominal dilatation, paraplegia, dehydration, or severe weight loss. Percentage increase in lifespan (%ILS) was calculated based on both median and mean survival to humane endpoint, as previously described . For more detailed procedures see Supporting Information.…”
Section: Methodsmentioning
confidence: 99%
“…Idasanutlin (RO5503781/RG7388), a pyrrolidine and second generation MDM2 antagonist from Hoffman‐La Roche has enhanced potency, selectivity and bioavailability, and has been developed in both oral and intravenous (IV; RO6839921) formulations . To overcome tolerability issues with daily administration, intermittent schedules of idasanutlin, designed to enable bone marrow recovery, are being clinically evaluated in adult cancers both alone and in combination …”
Section: Introductionmentioning
confidence: 99%