ISSN:
1432-0843
Keywords:
Pharmacokinetics
;
Population
;
NONMEM
;
NPML
;
Docetaxel
;
Taxotere
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1–2 h) at various dose levels (70–115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl wasCl=BSA(θ1+θ2×AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh−1 m−2) and 37.2 l/h with interpatient coefficients of variation (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.2 l for NPML versus 124 l for NONMEM) and in terminal half-lives, notably the meant 1/2γ, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss andt 1/2γ, respectively. However, the NPML-estimated probability density function (pdf) oft 1/2γ, was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00685628
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