title: Dose selection, pharmacokinetics, and pharmacodynamics of BRAF inhibitor dabrafenib (GSK2118436).
abstract: OBJECTIVE
  Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose-response relationship.
  
  
  METHODS
  Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.
  
  
  RESULTS
  One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation-positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.
  
  
  CONCLUSIONS
  The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose-response relationship. A maximum tolerated dose for dabrafenib was not determined.
authors: Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. gerald.falchook@scresearch.net georgina.long@sydney.edu.au.
authors: Gerald S
authors: GS
authors: Falchook
authors: Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia. gerald.falchook@scresearch.net georgina.long@sydney.edu.au.
authors: Georgina V
authors: GV
authors: Long
authors: Moores Cancer Center, University of California San Diego, La Jolla, California.
authors: Razelle
authors: R
authors: Kurzrock
authors: Division of Cancer Medicine, Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Kevin B
authors: KB
authors: Kim
authors: GlaxoSmithKline Medicines Research Unit, Prince of Wales Hospital, Randwick, New South Wales, Australia.
authors: H-Tobias
authors: HT
authors: Arkenau
authors: Cancer Clinical Trials Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, South Australia, Australia.
authors: Michael P
authors: MP
authors: Brown
authors: Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, California.
authors: Omid
authors: O
authors: Hamid
authors: Drug Development Unit, Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, Tennessee.
authors: Jeffrey R
authors: JR
authors: Infante
authors: Cancer Council Trials and Sir Charles Gairdner Hospital and University of Western Australia, Perth, Western Australia, Australia.
authors: Michael
authors: M
authors: Millward
authors: Division of Medical Oncology, New York University School of Medicine, New York, New York.
authors: Anna
authors: A
authors: Pavlick
authors: Prince of Wales Clinical School, University of New South Wales, Randwick, Australia.
authors: Melvin T
authors: MT
authors: Chin
authors: Experimental Therapeutics/Immunotherapy, The Angeles Clinic and Research Institute, Los Angeles, California.
authors: Steven J
authors: SJ
authors: O'Day
authors: GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina.
authors: Samuel C
authors: SC
authors: Blackman
authors: GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina.
authors: C Martin
authors: CM
authors: Curtis
authors: GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina.
authors: Peter
authors: P
authors: Lebowitz
authors: GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina.
authors: Bo
authors: B
authors: Ma
authors: GlaxoSmithKline Research and Development, Philadelphia, Pennsylvania and Research Triangle Park, North Carolina.
authors: Daniele
authors: D
authors: Ouellet
authors: Melanoma Institute Australia and University of Sydney, New South Wales, Australia. Westmead Institute for Cancer Research, Westmead Millennium Institute, and Department of Medical Oncology, Westmead Hospital, Sydney, New South Wales, Australia.
authors: Richard F
authors: RF
authors: Kefford
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D010091:Oximes / Q000008:administration & dosage* / Q000009:adverse effects; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D016896:Treatment Outcome
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib