Population pharmacokinetics of docetaxel during phase I studies using nonlinear mixed-effect modeling and nonparametric maximum-likelihood estimation |
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Authors: | M C Launay-Iliadis R Bruno V Cosson J C Vergniol D Oulid-Aissa M Marty M Clavel M Aapro N Le Bail A Iliadis |
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Institution: | (1) INSERM U 278, 27 bd Jean Moulin, F-13385 Marseille Cédex 5, France;(2) Rhône-Poulenc Rorer, Drug Metabolism and Pharmacokinetics, 20 bd Raymond Aron, Box 58, F-92165 Antony Cédex, France;(3) Hôpital Saint-Louis, 1 av Claude Vellefaux, F-75010 Paris, France;(4) Centre Léon-Bérard, 28 rue Laënnec, F-69373 Lyon Cedex 08, France;(5) C.H.U.G., 24 rue Micheli du Crest, CH-1211 Genève, Switzerland;(6) Laboratoire de Pharmacocinétique et Toxicocinétique, Faculté de Pharmacie, 27 bd Jean Moulin, F-13385 Marseille Cédex 5, France;(7) Present address: European Institute of Oncology, Via Ripamonti 99, Milano, Italy |
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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( 1+ 2×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
1/2 , 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
1/2 , respectively. However, the NPML-estimated probability density function (pdf) oft
1/2 , 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. |
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Keywords: | Pharmacokinetics Population NONMEM NPML Docetaxel Taxotere |
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