title: A population pharmacokinetic meta-analysis of custirsen, an antisense oligonucleotide, in oncology patients and healthy subjects.
abstract: OBJECTIVE
  Custirsen (OGX-011/TV-1011), a second-generation antisense oligonucleotide that reduces clusterin production, is under investigation with chemotherapy in prostate and lung cancer. This meta-analysis evaluated the population pharmacokinetics (PK) of custirsen in cancer patients and healthy subjects.
  
  
  METHODS
  The population PK analysis used custirsen plasma concentrations from five Phase 1 studies, one Phase 1/2 study, and one Phase 3 study in two stages. Cancer patients received multiple doses of custirsen (40-640 mg intravenously over 120 min) with chemotherapy; healthy subjects received single or multiple doses (320-640 mg). An interim population PK model was developed using a nonlinear mixed-effect approach incorporating data from four Phase 1 or 1/2 studies, followed by model refinement and inclusion of two Phase 1 and one Phase 3 studies.
  
  
  RESULTS
  The final model was developed with 5588 concentrations from 631 subjects with doses of 160-640 mg. Custirsen PK was adequately described by a three-compartment model with first-order elimination. For a representative 66-year-old individual with body weight 82 kg and serum creatinine level 0.933 mg dl-1, the estimated typical (95% CI) parameter values were clearance (CL) = 2.36 (2.30-2.42) l h-1, central volume of distribution (V1) = 6.08 (5.93-6.23) l, peripheral volume of distribution (V2) = 1.13 (1.01-1.25) l, volume of the second peripheral compartment (V3) = 15.8 (14.6-17.0) l, inter-compartmental clearance Q2= 0.0755 (0.0689-0.0821) l h-1, and Q3= 0.0573 (0.0532-0.0614) l h-1. Age, weight and serum creatinine were predictors of CL; age was a predictor of Q3.
  
  
  CONCLUSIONS
  A population PK model for custirsen was successfully developed in cancer patients and healthy subjects, including covariates contributing to variability in custirsen PK.
authors.affiliation: ICON, Marlow, Buckinghamshire, UK.
authors.forename: Alena Y
authors.initials: AY
authors.lastname: Edwards
authors.affiliation: Teva Pharmaceutical Industries Ltd., Netanya, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Elgart
authors.affiliation: ICON, Marlow, Buckinghamshire, UK.
authors.forename: Colm
authors.initials: C
authors.lastname: Farrell
authors.affiliation: Teva Pharmaceutical Industries Ltd., Netanya, Israel.
authors.forename: Ofra
authors.initials: O
authors.lastname: Barnett-Griness
authors.affiliation: Teva Pharmaceutical Industries Ltd., Frazer, Pennsylvania, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Rabinovich-Guilatt
authors.affiliation: Teva Pharmaceutical Industries Ltd., Netanya, Israel.
authors.forename: Ofer
authors.initials: O
authors.lastname: Spiegelstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data*; D004305:Dose-Response Relationship, Drug; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood; D017711:Nonlinear Dynamics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D013873:Thionucleotides / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: C503781:OGX-011; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides
keywords: Custirsen; antisense oligonucleotide; clusterin; population pharmacokinetics