title: Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis.
abstract: OBJECTIVE
  The purpose was to determine the exposure-response relationship of everolimus in patients with angiomyolipoma from the EXIST-2 trial and to analyze the correlation between exposure and plasma concentrations of angiogenic biomarkers in these patients.
  
  
  METHODS
  One hundred and eighteen patients with angiomyolipoma associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (sLAM) were randomly assigned 2 : 1 to receive everolimus 10 mg (n = 79) or placebo (n = 39) once daily. Blood samples for determining everolimus concentration were collected at weeks 2, 4, 12, 24 and 48 during double-blind treatment. Plasma samples for biomarker analysis were collected at baseline and weeks 4, 12, 24, 36, 48 and at the end of treatment. Concentrations of eight angiogenic biomarkers associated with tumour growth were determined by enzyme-linked immunosorbent assay (ELISA).
  
  
  RESULTS
  Peak and trough concentrations of everolimus in blood remained stable over time and similar to those reported in other indications. Substantial pharmacodynamic effects were observed in the everolimus, but not placebo, arm for three biomarkers: After 24 weeks of treatment, reduction of vascular endothelial growth factor D (VEGF-D) and collagen type IV (COL-IV) (mean fold-changes with 95% confidence intervals [CI] were 0.36 [0.33, 0.40], and 0.54 [0.51, 0.57], respectively, P < 0.001 for both), along with increased VEGF-A (mean fold-change of 1.59 [1.39, 1.80], P < 0.001), were seen. Furthermore, baseline VEGF-D and COL-IV levels were associated with angiomyolipoma size at baseline and with angiomyolipoma response to everolimus.
  
  
  CONCLUSIONS
  These findings suggest that plasma angiogenic markers may provide an objective measure of patient response to everolimus.
authors.affiliation: Charité Universitätsmedizin, Berlin, Germany.
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.affiliation: Universitair Medisch Centrum, Utrecht, The Netherlands.
authors.forename: Bernard A
authors.initials: BA
authors.lastname: Zonnenberg
authors.affiliation: Minnesota Epilepsy Group, St Paul, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Frost
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Wing
authors.initials: W
authors.lastname: Cheung
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Shweta
authors.initials: S
authors.lastname: Urva
authors.affiliation: Novartis Pharma Corporation, S.A.S., Rueil-Malmaison, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brechenmacher
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Stein
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chen
authors.affiliation: Royal Sussex County Hospital, Brighton, UK.
authors.forename: John Christopher
authors.initials: JC
authors.lastname: Kingswood
authors.affiliation: Lebonheur Children's Hospital and the University of Tennessee, Memphis, Tennessee, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Bissler
mesh_terms: D000328:Adult; D018207:Angiomyolipoma / Q000150:complications / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D024141:Collagen Type IV / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004797:Enzyme-Linked Immunosorbent Assay; D000068338:Everolimus / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007680:Kidney Neoplasms / Q000150:complications / Q000188:drug therapy*; D018192:Lymphangioleiomyomatosis / Q000150:complications / Q000188:drug therapy*; D014402:Tuberous Sclerosis / Q000150:complications / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood; D042643:Vascular Endothelial Growth Factor D / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D024141:Collagen Type IV; C467484:VEGFA protein, human; C579459:VEGFD protein, human; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; D000068338:Everolimus
keywords: VEGF-D; angiomyolipoma; biomarkers; collagen-IV; lymphangioleiomyomatosis; tuberous sclerosis complex