title: Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Authors' Affiliations: Discovery Oncology; brian_x.higgins@Roche.com.
authors.forename: Brian
authors.initials: B
authors.lastname: Higgins
authors.affiliation: Drug Metabolism and Pharmacokinetics; and.
authors.forename: Kelli
authors.initials: K
authors.lastname: Glenn
authors.affiliation: Modeling and Simulation, Pharma Research and Early Development, Hoffmann-La Roche, Inc., Basel, Switzerland.
authors.forename: Antje
authors.initials: A
authors.lastname: Walz
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: Christian
authors.initials: C
authors.lastname: Tovar
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: Zoran
authors.initials: Z
authors.lastname: Filipovic
authors.affiliation: Drug Metabolism and Pharmacokinetics; and.
authors.forename: Sazzad
authors.initials: S
authors.lastname: Hussain
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: Edmund
authors.initials: E
authors.lastname: Lee
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kolinsky
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: Shahid
authors.initials: S
authors.lastname: Tannu
authors.affiliation: Non-Clinical Safety, Pharma Research and Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey; and.
authors.forename: Violeta
authors.initials: V
authors.lastname: Adames
authors.affiliation: Non-Clinical Safety, Pharma Research and Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey; and.
authors.forename: Rosario
authors.initials: R
authors.lastname: Garrido
authors.affiliation: Non-Clinical Safety, Pharma Research and Early Development, Hoffmann-La Roche, Inc., Nutley, New Jersey; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Linn
authors.affiliation: Modeling and Simulation, Pharma Research and Early Development, Hoffmann-La Roche, Inc., Basel, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Meille
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: David
authors.initials: D
authors.lastname: Heimbrook
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: Lyubomir
authors.initials: L
authors.lastname: Vassilev
authors.affiliation: Authors' Affiliations: Discovery Oncology;
authors.forename: Kathryn
authors.initials: K
authors.lastname: Packman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017209:Apoptosis; D001859:Bone Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D048288:Imidazolines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008819:Mice, Nude; D012516:Osteosarcoma / Q000188:drug therapy; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors*; D011759:Pyrrolidines / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D062366:para-Aminobenzoates / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D048288:Imidazolines; D011759:Pyrrolidines; C579783:RG7112; C586849:RG7388; D062366:para-Aminobenzoates; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2