title: Population pharmacokinetic model of PI-88, a heparanase inhibitor.
abstract: OBJECTIVE
  The aim of this study was to investigate typical population pharmacokinetic (PK) parameters, potential covariates, and interindividual and residual variabilities of PI-88, a heparanase endoglycosidase enzyme inhibitor being developed for the treatment of cancer.
  
  
  METHODS
  A population PK model of PI-88 was developed and evaluated using nonlinear mixed effects modeling (NONMEM). Plasma concentration versus time data was obtained from a total of 76 subjects that participated in phase I trials of PI-88 delivered subcutaneously (SC) at doses ranging from 80 to 315 mg. Overall, the PK effects of 12 clinical covariates were evaluated, including weight, age, creatinine clearance, body surface area, body mass index, sex, cancer (vs. healthy subject), docetaxel coadministration, prior chemotherapy, prior investigational therapy, prior radiotherapy and prior surgery.
  
  
  RESULTS
  Population PK analysis of the data-set showed that apparent clearance (CL/F) and apparent volume of distribution (V/F) of PI-88 were positively correlated with body surface area and the absorption rate constant (KA) was positively correlated with body mass index. In addition, CL/F was found to be significantly lower in patients with malignancies versus healthy subjects. By incorporating these covariates into the PK parameter equations, the interindividual variability of CL/F was reduced from 30.6 to 20.2% (decrease of 34%), V/F was reduced from 31.4 to 20.7% (decrease of 34.1%) and KA was reduced from 52.6 to 46.2% (decrease of 12.2%).
  
  
  CONCLUSIONS
  This population PK model indicates that the PK variability of PI-88 can be significantly reduced by taking BSA into account when dosing this drug SC.
authors.affiliation: Animal Cancer Center, Department of Clinical Sciences, Colorado State University, 1620 Campus Delivery, Fort Collins, CO 80523-1620, USA. susan.hudachek@colostate.edu
authors.forename: Susan F
authors.initials: SF
authors.lastname: Hudachek
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: Barbara
authors.initials: B
authors.lastname: Hicks
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D019540:Area Under Curve; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009844:Oligosaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013997:Time Factors; D055815:Young Adult; D000099175:Heparanase
chemical_list: D004791:Enzyme Inhibitors; D005966:Glucuronidase; D009844:Oligosaccharides; D000099175:Heparanase; C120158:phosphomannopentaose sulfate