title: Population pharmacokinetics and exposure-response of trametinib, a MEK inhibitor, in patients with BRAF V600 mutation-positive melanoma.
abstract: OBJECTIVE
  To characterize the pharmacokinetics of oral trametinib, a first in class MEK inhibitor, identify covariates, and describe the relationship between exposure and clinical effects in patients with BRAF V600 metastatic melanoma.
  
  
  METHODS
  Trametinib concentrations obtained in three clinical studies were included in the population pharmacokinetic analysis. Trametinib 2 mg once daily was administered in the Phase 2 and 3 studies. The impact of exposure [trough (C min) or average concentration] on response rates and progression-free survival (PFS) was examined.
  
  
  RESULTS
  Plasma concentrations (n = 3120) obtained in 493 patients were described using a two-compartment model. Trametinib oral clearance was lower in women relative to men (1.26-fold) and increased with body weight. There was no significant effect of age, mild or moderate renal impairment, or mild hepatic impairment on oral clearance. Between-subject variability was low (24 %). The number of responders was consistent across median exposure range, although tended to be lower at trough concentration <10 ng/mL. Disease stage was found to be a significant predictor of response with a lower response rate in patients with disease stage of M1c. Lactate dehydrogenase was significant in the analysis of PFS. Patients with observed C min above the median had longer PFS than those below median based on Phase 2 study (median 10.6 ng/mL), while the effect of exposure was not statistically significant in the Phase 3 study (median 13.6 ng/mL).
  
  
  CONCLUSIONS
  No dosage adjustments are required with any of the covariates tested. Clinical efficacy was associated with trametinib trough concentrations greater than 10 ng/mL.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA. douelle2@its.jnj.com.|Janssen Research & Development, Spring House, PA, USA. douelle2@its.jnj.com.
authors.forename: Daniele
authors.initials: D
authors.lastname: Ouellet
authors.affiliation: Certara Strategic Consulting, Montreal, Canada.
authors.forename: Nastya
authors.initials: N
authors.lastname: Kassir
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.|Inncelerex,, Jersey City, NJ, USA.
authors.forename: Joannellyn
authors.initials: J
authors.lastname: Chiu
authors.affiliation: Certara Strategic Consulting, Montreal, Canada.
authors.forename: Mohamad-Samer
authors.initials: MS
authors.lastname: Mouksassi
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.|Genentech, South San Francisco, CA, USA.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Leonowens
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.|Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Cox
authors.affiliation: Incyte Corporation, Wilmington, DE, USA.
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: DeMarini
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.|Janssen Research & Development, Spring House, PA, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Gardner
authors.affiliation: Janssen Research & Development, Spring House, PA, USA.|Incyte Corporation, Wilmington, DE, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Crist
authors.affiliation: Janssen Research & Development, Spring House, PA, USA.|Incyte Corporation, Wilmington, DE, USA.
authors.forename: Kiran
authors.initials: K
authors.lastname: Patel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011728:Pyridones / Q000493:pharmacokinetics*; D011744:Pyrimidinones / Q000493:pharmacokinetics*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Exposure–response; MEK inhibitor; Melanoma; NONMEM; Pharmacokinetics