title: Population pharmacokinetic modeling of idelalisib, a novel PI3Kδ inhibitor, in healthy subjects and patients with hematologic malignancies.
abstract: OBJECTIVE
  Idelalisib is a potent PI3Kδ inhibitor that was recently approved for treating hematologic malignancies. The objective of this analysis was to develop a population pharmacokinetic model for idelalisib and its inactive metabolite GS-563117 and to evaluate the impact of covariates on idelalisib/GS-563117 PK.
  
  
  METHODS
  Data from 10 phase I or II studies in healthy volunteers or patients with hematologic malignancies (n = 736) were analyzed using NONMEM. Stepwise forward addition followed by backward elimination was implemented in the covariate (age, gender, race, body weight, baseline CLcr, AST, ALT, disease status, and type of cancer) model building process. Various model assessment methods were used to evaluate the models.
  
  
  RESULTS
  Idelalisib plasma PK was best described by a two-compartment model with first-order absorption, first-order elimination from the central compartment, and a lag time. A nonlinear relationship between dose and relative bioavailability was included in the final model. Two statistically significant covariates were identified and incorporated into the final model: health status (healthy vs. patient) on CL/F and Q/F and body weight on CL/F. Despite being a statistically significant covariate, the effect of body weight on idelalisib exposures was weak, as evidenced by minor changes of steady-state exposure (C trough: 16%; AUC and C max: 10%) for a patient with extreme body weight (5th and 95th percentile) relative to the typical patient, and not considered to be clinically relevant.
  
  
  CONCLUSIONS
  PopPK models were developed to adequately describe the plasma concentrations of idelalisib and GS-563117. There were no covariate that had a clinically meaningful impact on idelalisib or GS-563117 exposure.
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, USA. feng.jin@gilead.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.affiliation: Quantitative Solutions, LP., Menlo Park, CA, USA.
authors.forename: Yuying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: CTI Biopharma, Seattle, WA, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Onyx Pharmaceuticals, South San Francisco, CA, USA.
authors.forename: Lorna
authors.initials: L
authors.lastname: Fang
authors.affiliation: Gilead Sciences, Inc., Seattle, WA, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.affiliation: Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA, USA.
authors.forename: Srini
authors.initials: S
authors.lastname: Ramanathan
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D016022:Case-Control Studies; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D052999:Quinazolinones / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib
keywords: Covariates; Idelalisib; PI3Kδ; Population pharmacokinetics