title: Bridging the gap between preclinical and clinical studies using pharmacokinetic-pharmacodynamic modeling: an analysis of GDC-0973, a MEK inhibitor.
abstract: OBJECTIVE
  GDC-0973 is a potent and selective mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor. Pharmacokinetic-pharmacodynamic (PK-PD) modeling was used to relate GDC-0973 plasma and tumor concentrations, tumor pharmacodynamics and antitumor efficacy to establish pharmacokinetic endpoints and predict active doses in the clinic.
  
  
  METHODS
  A PK-PD model was used to characterize GDC-0973 tumor disposition and in vivo potency in WM-266-4 xenograft mice. Simulations were conducted using the PK-PD model along with human pharmacokinetics to identify a target plasma concentration and predict active doses. In vivo potency and antitumor efficacy were characterized in A375 melanoma xenograft mice, and a population-based integrated PK-PD-efficacy model was used to relate tumor pharmacodynamics (%pERK decrease) to antitumor activity.
  
  
  RESULTS
  GDC-0973 showed a sustained tumor pharmacodynamic response due to longer residence in tumor than in plasma. Following single doses of GDC-0973, estimated in vivo IC(50) values of %pERK decrease based on tumor concentrations in xenograft mice were 0.78 (WM-266-4) and 0.52 μmol/L (A375). Following multiple doses of GDC-0973, the estimated in vivo IC(50) value in WM-266-4 increased (3.89 μmol/L). Human simulations predicted a minimum target plasma concentration of 83 nmol/L and an active dose range of 28 to 112 mg. The steep relationship between tumor pharmacodynamics (%pERK decrease) and antitumor efficacy suggests a pathway modulation threshold beyond which antitumor efficacy switches on.
  
  
  CONCLUSIONS
  Clinical observations of %pERK decrease and antitumor activity were consistent with model predictions. This article illustrates how PK-PD modeling can improve the translation of preclinical data to humans by providing a means to integrate preclinical and early clinical data.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Genentech, Inc., 1 DNA Way, MS 412a, South San Francisco, CA 94080, USA. wong.harvey@gene.com
authors.forename: Harvey
authors.initials: H
authors.lastname: Wong
authors.forename: Laurent
authors.initials: L
authors.lastname: Vernillet
authors.forename: Amy
authors.initials: A
authors.lastname: Peterson
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ware
authors.forename: Lillian
authors.initials: L
authors.lastname: Lee
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Martini
authors.forename: Peiwen
authors.initials: P
authors.lastname: Yu
authors.forename: Congfen
authors.initials: C
authors.lastname: Li
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Del Rosario
authors.forename: Edna F
authors.initials: EF
authors.lastname: Choo
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Yongchang
authors.initials: Y
authors.lastname: Shi
authors.forename: Blake T
authors.initials: BT
authors.lastname: Aftab
authors.forename: Ron
authors.initials: R
authors.lastname: Aoyama
authors.forename: Sanh Tan
authors.initials: ST
authors.lastname: Lam
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: John
authors.initials: J
authors.lastname: Prescott
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001384:Azetidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology; D008954:Models, Biological; D010880:Piperidines / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001384:Azetidines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; C574276:cobimetinib