Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors

Amita Patnaik, Anthony Tolcher, Murali Beeram, John Nemunaitis, Glen J. Weiss, Kapil Bhalla, Manish Agrawal, Gwen Nichols, Steven Middleton, Anna Beryozkina, Nenad Sarapa, Richard Peck, Jianguo Zhi

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Purpose: RG7112, the first selective small-molecule MDM2 antagonist in clinical testing, is a non-genotoxic oral p53 activator. To optimize its dose and schedule, a number of clinical pharmacology characteristics were explored in this multicenter trial in patients with advanced solid tumors. Method: In part 1, the impact of high-energy/high-fat meal and formulations (crystalline and amorphous) on relative bioavailability was examined in single-dose crossover designs. In part 2, schedule optimization (4 schedules of drug administration under fasting condition and 2 cohorts with liquid supplementation) was investigated in parallel, dose escalation designs. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) including MIC-1 elevation and platelet reduction, and safety/tolerability. Results: With a single-dose treatment, a high-fat/high-energy meal and a new formulation under fasting condition, respectively, enhanced overall bioavailability of RG7112 slightly over twofold. Following multiple-dose administrations, all four schedules yielded the comparable per-cycle (28-d) exposure (AUC), as designed; liquid supplements also enhanced bioavailability. High-dose treatments of consecutive daily dosing for 5 and 3 days resulted in higher on-treatment-day exposure to RG7112 than both weekly and low-dose/long-duration (20-day) daily schedules. Serum MIC-1 and blood platelet profiles showed similar patterns to those of PK when the clinical pharmacology conditions were varied, suggesting the relative importance of treatment-day exposure than overall per-cycle AUC. Conclusion: Food (both high-fat and low-fat meals) and new formulation enhanced bioavailability. High-dose consecutive daily treatment for 3-5 days is superior to weekly and low-dose/long-duration (20-day) daily schedules in yielding the sufficiently high drug exposure and PD effects potentially required for cancer treatment efficacy.

Original languageEnglish (US)
Pages (from-to)587-595
Number of pages9
JournalCancer Chemotherapy and Pharmacology
Volume76
Issue number3
DOIs
StatePublished - Sep 21 2015

Keywords

  • Food effect
  • Formulation change
  • MDM2 antagonist
  • Schedule optimization

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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