POPULATION PHARMACOKINETICS OF DOCETAXEL DURING PHASE-I STUDIES USINGNONLINEAR MIXED EFFECT MODELING AND NONPARAMETRIC MAXIMUM-LIKELIHOOD-ESTIMATION

Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1-2h) at various dose levels (70-115 mg/m(2), the maxi mum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other usin g NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population param eters, including clearance (Cl) and interindividual variability; and f ind 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 ty pe of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl was Cl = BSA(theta 1 + theta 2 x AGE), expressing Cl (in liters per hour) directly as a f unction of body surface area. Only these two covariates were considere d in the NPML analysis to confirm the results found by NONMEM. Using N ONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m(2 ))] and NPML, docetaxel Cl was estimated to be 35.61/h (21.21 h(-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 a n additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.21 for NPML ver sus 1241 for NONMEM) and in terminal half-lives, notably the mean t(1/ 2 gamma), 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 and t(1 /2 gamma), respectively. However, the NPML-estimated probability densi ty function (pdf) of t(1/2 gamma), was bimodal (5 and 11.4 h), probabl y due to the imbalance of the data. Both analyses suggest a similar ma gnitude of mean Cl decrease with small BSA and advanced age.