title: Optimising the combination dosing strategy of abemaciclib and vemurafenib in BRAF-mutated melanoma xenograft tumours.
abstract: BACKGROUND
  Resistance to BRAF inhibition is a major cause of treatment failure for BRAF-mutated metastatic melanoma patients. Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, overcomes this resistance in xenograft tumours and offers a promising drug combination. The present work aims to characterise the quantitative pharmacology of the abemaciclib/vemurafenib combination using a semimechanistic pharmacokinetic/pharmacodynamic modelling approach and to identify an optimum dosing regimen for potential clinical evaluation.
  
  
  METHODS
  A PK/biomarker model was developed to connect abemaciclib/vemurafenib concentrations to changes in MAPK and cell cycle pathway biomarkers in A375 BRAF-mutated melanoma xenografts. Resultant tumour growth inhibition was described by relating (i) MAPK pathway inhibition to apoptosis, (ii) mitotic cell density to tumour growth and, under resistant conditions, (iii) retinoblastoma protein inhibition to cell survival.
  
  
  RESULTS
  The model successfully described vemurafenib/abemaciclib-mediated changes in MAPK pathway and cell cycle biomarkers. Initial tumour shrinkage by vemurafenib, acquisition of resistance and subsequent abemaciclib-mediated efficacy were successfully captured and externally validated. Model simulations illustrate the benefit of intermittent vemurafenib therapy over continuous treatment, and indicate that continuous abemaciclib in combination with intermittent vemurafenib offers the potential for considerable tumour regression.
  
  
  CONCLUSIONS
  The quantitative pharmacology of the abemaciclib/vemurafenib combination was successfully characterised and an optimised, clinically-relevant dosing strategy was identified.
authors.affiliation: Global PK/PD, Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Sonya C
authors.initials: SC
authors.lastname: Tate
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Burke
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Daisy
authors.initials: D
authors.lastname: Hartman
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Palaniappan
authors.initials: P
authors.lastname: Kulanthaivel
authors.affiliation: Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beckmann
authors.affiliation: Global PK/PD, Eli Lilly and Company, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK.
authors.forename: Damien M
authors.initials: DM
authors.lastname: Cronier
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001562:Benzimidazoles / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000493:pharmacokinetics; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D001562:Benzimidazoles; D014408:Biomarkers, Tumor; D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; C000590451:abemaciclib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf