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Population Pharmacokinetics of the Novel Anticancer Agent E7070 During Four Phase I Studies: Model Building and Validation

From the Department of Pharmacy and Pharmacology and Department of Medical Oncology, the Netherlands Cancer Institute/Slotervaart Hospital; and NDDO Oncology/Free University Hospital, Amsterdam; UMC St Radboud, Nijmegen; and Faculty of Pharmacy, Utrecht University, Utrecht, the Netherlands; Institut Gustave Roussy, Villejuif, Centre Claudius Regaud, Toulouse; Centre Regional Leon Berard, Lyon; and Centre René Gauducheau, Nantes, France; LBI-ACR and KFJ-Spital, Vienna, Austria; University Hospital Gasthuisberg, Leuven, Belgium; and Eisai Ltd, London, United Kingdom.

Address correspondence to Ch. van Kesteren, MD, Department of Pharmacy and Pharmacology, the Netherlands Cancer Institute/Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, the Netherlands; email: apcks{at}slz.nl

PURPOSE: N-(3-Chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070) is a novel sulfonamide anticancer agent currently in phase II clinical development for the treatment of solid tumors. Four phase I studies have been finalized, with E7070 administered at four different treatment schedules to identify the maximum-tolerated dose and the dose-limiting toxicities. Pharmacokinetic analyses of all studies revealed E7070 to have nonlinear pharmacokinetics. A population pharmacokinetic model was designed and validated to describe the pharmacokinetics of E7070 at all four treatment schedules and to identify the possible influences of patient characteristics on the pharmacokinetic parameters.

PATIENTS AND METHODS: Plasma concentration-time data of all patients (n = 143) were fitted to several pharmacokinetic models using NONMEM. Seventeen covariables were investigated for their relation with individual pharmacokinetic parameters. A bootstrap procedure was performed to check the validity of the model.

RESULTS: The data were best described using a three-compartment model with nonlinear distribution to a peripheral compartment and two parallel pathways of elimination from the central compartment: a linear and a saturable pathway. Body-surface area (BSA) was significantly correlated to both the volume of distribution of the central compartment and to the maximal elimination capacity. The fits of 500 bootstrap replicates of the data set demonstrated the robustness of the developed population pharmacokinetic model.

CONCLUSION: A population pharmacokinetic model has been designed and validated that accurately describes the data of four phase I studies with E7070. Furthermore, it has been demonstrated that BSA-guided dosing for E7070 is important.

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