title: Semi-physiological model describing the hematological toxicity of the anti-cancer agent indisulam.
abstract: Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
authors.forename: Charlotte
authors.initials: C
authors.lastname: van Kesteren
authors.forename: Anthe S
authors.initials: AS
authors.lastname: Zandvliet
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Ron A A
authors.initials: RA
authors.lastname: Mathôt
authors.forename: Cornelis J A
authors.initials: CJ
authors.lastname: Punt
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Armand
authors.forename: Eric
authors.initials: E
authors.lastname: Raymond
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
authors.forename: Christian
authors.initials: C
authors.lastname: Dittrich
authors.forename: Herlinde
authors.initials: H
authors.lastname: Dumez
authors.forename: Henri H
authors.initials: HH
authors.lastname: Roché
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Droz
authors.forename: Miroslav
authors.initials: M
authors.lastname: Ravic
authors.forename: S Murray
authors.initials: SM
authors.lastname: Yule
authors.forename: Jantien
authors.initials: J
authors.lastname: Wanders
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Pierre
authors.initials: P
authors.lastname: Fumoleau
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009503:Neutropenia / Q000139:chemically induced*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects*; D013921:Thrombocytopenia / Q000139:chemically induced*
chemical_list: D000970:Antineoplastic Agents; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides