title: Integrated analysis of preclinical data to support the design of the first in man study of LY2181308, a second generation antisense oligonucleotide.
abstract: OBJECTIVE
  To predict the concentration and target inhibition profiles of the survivin inhibitor antisense oligonucleotide LY2181308 in humans.
  
  
  METHODS
  An indirect pharmacokinetic/pharmacodynamic (PK/PD) model was built to predict the inhibition of survivin mRNA and protein in humans following LY2181308 dosing. Plasma and tissue PK data from cynomolgus monkeys were analyzed by non-linear mixed effect modelling techniques. Human PK parameters were predicted using allometric scaling. Assumptions about the pharmacodynamic parameters were made based upon the target and tumour growth inhibition data from mouse xenograft models. This enabled the prediction of the clinical PK/PD profiles.
  
  
  RESULTS
  Following a 750 mg dose, LY2181308 tumour concentrations ranging from 18.8 to 54µgg(-1) were predicted to lead to 50 to 90% target inhibition. In humans, LY2181308 tumour concentrations fro 13.9 to 52.8µgg(-1) (n=4, LY2181308 750mg) were observed associated with a median survivin mRNA and protein inhibition of 20%±34 (SD) (n=9) and 23%±63 (SD) (n=10), respectively. The human PK parameters were adequately estimated: central V(d) , 4.09 l (90% CI, 3.6, 4.95), distribution clearances, 2.54 (2.36, 2.71), 0.0608 (0.033, 0.6) and 1.67 (1.07, 2.00)lh(-1) , peripheral V(d) s, 25 900 (19 070, 37 200), 0.936 (0.745, 2.07) and 2.51 (1.01, 2.922)l, mean elimination clearance 23.1lh(-1) (5.6, 33.4) and mean terminal half-life, 32.7 days (range 22-52 days).
  
  
  CONCLUSIONS
  The model reasonably predicted LY2181308 PK in humans. Overall, the integration of preclinical PK/PD data enabled to appropriately predict dose and dosing regimen of LY2181308 in humans with pharmacologically relevant survivin inhibition achieved at 750mg.
authors.affiliation: Eli Lilly and Company, 13 rue Pages, Suresnes, 92158 France Eli Lilly and Company, Erlwood Manor, Sunninghill Road, Windlesham, GU20 6PH, UK. Callies_sophie@lilly.com
authors.forename: Sophie
authors.initials: S
authors.lastname: Callies
authors.forename: Valérie
authors.initials: V
authors.lastname: André
authors.forename: Bharvin
authors.initials: B
authors.lastname: Patel
authors.forename: David
authors.initials: D
authors.lastname: Waters
authors.forename: Paul
authors.initials: P
authors.lastname: Francis
authors.forename: Michael
authors.initials: M
authors.lastname: Burgess
authors.forename: Michael
authors.initials: M
authors.lastname: Lahn
mesh_terms: D000818:Animals; D001835:Body Weight; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015507:Drugs, Investigational / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy*; D009841:Oligonucleotides / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D012107:Research Design
chemical_list: D015507:Drugs, Investigational; C529350:LY 2181308; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger