Purpose: To evaluate the population pharmacokinetics of pemetrexed disodium
in cancer patients enrolled in four different open-label, multicenter, non
randomized phase II studies. Methods: Pemetrexed disodium was administered
as a 10-min intravenous infusion (600 mg/m(2)) every 21 days. A total of fo
ur blood samples were to be collected each cycle per patient (n = 103 patie
nts) during cycles 1 and 3. Plasma concentration-time data were analyzed by
nonlinear mixed-effect modeling using NONMEM to estimate pemetrexed disodi
um pharmacokinetic parameters (mean, and between- and within-patient variab
ility) as well as relationships between the pharmacokinetic parameters and
various patient-specific factors (demographic and physiologic data). Result
s/Conclusions: The pharmacokinetics of pemetrexed disodium were best charac
terized by a two-compartment model with initial distribution and terminal e
limination 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 c
reatinine clearance (CrCL) with a slope of 0.0292. Typical values of centra
l volume (V-c), distributional CL (Q), and peripheral volume (V-p) were 11.
3 l, 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 additi
ve/proportional error model was used to describe residual variability, with
a coefficient of variation of 23.7% for the proportional component and a s
tandard deviation of 0.0410 mu g/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 alb
umin were significant factors on V-p. In conclusion, population pharmacokin
etic modeling revealed relationships between pharmacokinetic parameters and
various patient specific factors.