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: Charlotte van Kesteren, Anthe S Zandvliet, Mats O Karlsson, Ron A A Mathôt, Cornelis J A Punt, Jean-Pierre Armand, Eric Raymond, Alwin D R Huitema, Christian Dittrich, Herlinde Dumez, Henri H Roché, Jean-Pierre Droz, Miroslav Ravic, S Murray Yule, Jantien Wanders, Jos H Beijnen, Pierre Fumoleau, Jan H M Schellens
• Journal: Investigational new drugs (Invest New Drugs) Vol. 23 Issue 3 Pg. 225-34 (Jun 2005) ISSN: 0167-6997 [Print] United States
• PMID: 15868378 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide
• Sulfonamides

Topics

• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects)
• Clinical Trials, Phase I as Topic
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Models, Biological
• Neutropenia (chemically induced)
• Sulfonamides (administration & dosage, adverse effects)
• Thrombocytopenia (chemically induced)