title: Clinical pharmacology characterization of RG7112, an MDM2 antagonist, in patients with advanced solid tumors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: START, San Antonio, TX, USA.
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
authors.forename: Anthony
authors.initials: A
authors.lastname: Tolcher
authors.forename: Murali
authors.initials: M
authors.lastname: Beeram
authors.forename: John
authors.initials: J
authors.lastname: Nemunaitis
authors.forename: Glen J
authors.initials: GJ
authors.lastname: Weiss
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
authors.forename: Manish
authors.initials: M
authors.lastname: Agrawal
authors.forename: Gwen
authors.initials: G
authors.lastname: Nichols
authors.forename: Steven
authors.initials: S
authors.lastname: Middleton
authors.forename: Anna
authors.initials: A
authors.lastname: Beryozkina
authors.forename: Nenad
authors.initials: N
authors.lastname: Sarapa
authors.forename: Richard
authors.initials: R
authors.lastname: Peck
authors.forename: Jianguo
authors.initials: J
authors.lastname: Zhi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001682:Biological Availability; D004334:Drug Administration Schedule; D005215:Fasting / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D006801:Humans; D048288:Imidazolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D019518:Postprandial Period; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D055815:Young Adult
chemical_list: D048288:Imidazolines; C579783:RG7112; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2