title: Population pharmacokinetics of pemetrexed disodium (ALIMTA) in patients with cancer.
abstract: OBJECTIVE
  To evaluate the population pharmacokinetics of pemetrexed disodium in cancer patients enrolled in four different open-label, multicenter, nonrandomized phase II studies.
  
  
  METHODS
  Pemetrexed disodium was administered as a 10-min intravenous infusion (600 mg/m2) every 21 days. A total of four blood samples were to be collected each cycle per patient (n= 103 patients) during cycles 1 and 3. Plasma concentration-time data were analyzed by nonlinear mixed-effect modeling using NONMEM to estimate pemetrexed disodium pharmacokinetic parameters (mean, and between- and within-patient variability) as well as relationships between the pharmacokinetic parameters and various patient-specific factors (demographic and physiologic data).
  
  
  CONCLUSIONS
  The pharmacokinetics of pemetrexed disodium were best characterized by a two-compartment model with initial distribution and terminal elimination half-lives of 0.63 h and 2.73 h, respectively. The typical value of systemic clearance (CL) in liters per hour included a relationship to creatinine clearance (CrCL) with a slope of 0.0292. Typical values of central volume (V(c)), distributional CL (Q), and peripheral volume (V(p)) were 11.3 1, 3.21 l/h, and 5.20 l, respectively. Between-patient variability was 19.6%, 15.6%, and 21.7% for CL, V(c), and V(p), respectively. A combined additive/proportional error model was used to describe residual variability, with a coefficient of variation of 23.7% for the proportional component and a standard deviation of 0.0410 microg/ml for the additive component. Significant patient-specific factors on CL were calculated CrCL, body weight, and to a lesser extent alanine transaminase and folate deficiency. Gender and body weight were significant factors on V(c) while both body surface area and albumin were significant factors on V(p). In conclusion, population pharmacokinetic modeling revealed relationships between pharmacokinetic parameters and various patient specific factors.
authors.affiliation: Phoenix International Life Sciences Inc, Saint-Laurent, Québec, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Ouellet
authors.forename: A P
authors.initials: AP
authors.lastname: Periclou
authors.forename: R D
authors.initials: RD
authors.lastname: Johnson
authors.forename: J R
authors.initials: JR
authors.lastname: Woodworth
authors.forename: R L
authors.initials: RL
authors.lastname: Lalonde
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics*; D001825:Body Fluid Compartments; D017322:Clinical Trials, Phase II as Topic; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005493:Folic Acid Antagonists / Q000097:blood / Q000493:pharmacokinetics; D005971:Glutamates / Q000097:blood / Q000493:pharmacokinetics*; D006147:Guanine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007206:Individuality; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D009369:Neoplasms / Q000097:blood*; D000068437:Pemetrexed; D016032:Randomized Controlled Trials as Topic
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine