title: Population pharmacokinetics and pharmacodynamics of BYL719, a phosphoinositide 3-kinase antagonist, in adult patients with advanced solid malignancies.
abstract: OBJECTIVE
  The aim was to characterize the population pharmacokinetics of BYL719 in cancer patients and assess the time course of tumour response in relation to drug exposure and dosing schedule.
  
  
  METHODS
  Plasma samples and longitudinal tumour size measurements were collected from 60 patients with advanced solid malignancies who received oral BYL719 once daily (30-450 mg) or twice daily at 120 mg or 200 mg. Non-linear mixed effect modelling was employed to develop the population pharmacokinetic and pharmacodynamic model.
  
  
  RESULTS
  The pharmacokinetics were best described by a one compartment disposition model and transit compartments accounting for the lag time in absorption. The typical population oral clearance and volume of distribution estimates with their between-subject variability (BSV) were 10 l h(-1) (BSV 26%) and 108 l (BSV 28%), respectively. The estimated optimal number of transit compartments was 8.1, with a mean transit time to the absorption compartment of 1.28 h (BSV 32%). The between-occasion variability in the rate and extent of absorption was 46% and 26%, respectively. Tumour growth was modelled using a turnover model characterized by a zero order growth rate of 0.581 cm week(1) and a first order death rate of 0.0123 week(-1) . BYL719 inhibited tumour growth with an IC50 of 100 ng ml(-1) (BSV 154%). Model-based predictions showed potential for additional anti-tumour activity of twice daily dosing at total daily dose below 400 mg, but a loss of efficacy if administered less frequently than once daily.
  
  
  CONCLUSIONS
  The proposed model provides a valuable approach for planning future clinical studies and for designing optimized dosing regimens with BYL719.
authors.affiliation: Oncology Clinical Pharmacology, Novartis Pharmaceuticals A.G., Basel, Switzerland.
authors.forename: Stefan S
authors.initials: SS
authors.lastname: De Buck
authors.forename: Annamaria
authors.initials: A
authors.lastname: Jakab
authors.forename: Markus
authors.initials: M
authors.lastname: Boehm
authors.forename: Douglas
authors.initials: D
authors.lastname: Bootle
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.forename: Cornelia
authors.initials: C
authors.lastname: Quadt
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Goggin
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017711:Nonlinear Dynamics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013844:Thiazoles; C585539:Alpelisib
keywords: BYL719; RECIST; cancer; phosphoinositide 3-kinase; population pharmacokinetics; transit compartment