AIM: Chemotherapy with indisulam causes myelosuppression. This study aimed to evaluate the influence of patient-related covariates on pharmacokinetics and pharmacodynamics, to identify patients at risk for severe myelosuppression and to develop a dosing algorithm for treatment optimization. METHODS: Pharmacokinetic and pharmacodynamic data of 412 patients were available. Non-linear mixed effects modeling was used to determine the relative risk of dose-limiting myelosuppression for various covariates (demographics, physical condition, prior treatment, comedication, CYP2C genotype and biochemistry). RESULTS: Body surface area (BSA), race and CYP2C genotype had a significant impact on indisulam elimination (P < 0.001). Low BSA, Japanese race, variant CYP2C genotype, low baseline neutrophil and thrombocyte counts and female sex were clinically relevant risk factors of dose-limiting myelosuppression (RR > 1.1). A dosing strategy was developed to optimize treatment for patient subgroups. CONCLUSIONS: This study has identified covariates related to an increased risk of myelosuppression after indisulam therapy. Dose individualization may contribute to treatment optimization.
AIM: Chemotherapy with indisulam causes myelosuppression. This study aimed to evaluate the influence of patient-related covariates on pharmacokinetics and pharmacodynamics, to identify patients at risk for severe myelosuppression and to develop a dosing algorithm for treatment optimization. METHODS: Pharmacokinetic and pharmacodynamic data of 412 patients were available. Non-linear mixed effects modeling was used to determine the relative risk of dose-limiting myelosuppression for various covariates (demographics, physical condition, prior treatment, comedication, CYP2C genotype and biochemistry). RESULTS: Body surface area (BSA), race and CYP2C genotype had a significant impact on indisulam elimination (P < 0.001). Low BSA, Japanese race, variant CYP2C genotype, low baseline neutrophil and thrombocyte counts and female sex were clinically relevant risk factors of dose-limiting myelosuppression (RR > 1.1). A dosing strategy was developed to optimize treatment for patient subgroups. CONCLUSIONS: This study has identified covariates related to an increased risk of myelosuppression after indisulam therapy. Dose individualization may contribute to treatment optimization.
Authors: A S Zandvliet; W S Siegel-Lakhai; J H Beijnen; W Copalu; M-C Etienne-Grimaldi; G Milano; J H M Schellens; A D R Huitema Journal: Clin Pharmacol Ther Date: 2007-09-12 Impact factor: 6.875
Authors: Anthe S Zandvliet; William Copalu; Jan H M Schellens; Jos H Beijnen; Alwin D R Huitema Journal: Drug Metab Dispos Date: 2006-03-24 Impact factor: 3.922
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: Invest New Drugs Date: 2005-06 Impact factor: 3.850
Authors: Robert I Haddad; Lisa J Weinstein; Tad J Wieczorek; Nandita Bhattacharya; Harry Raftopoulos; Martin W Oster; Xinxin Zhang; Vaughan M Latham; Rosemary Costello; Jarrod Faucher; Carolyn DeRosa; Murray Yule; Linda P Miller; Massimo Loda; Marshall R Posner; Geoffrey I Shapiro Journal: Clin Cancer Res Date: 2004-07-15 Impact factor: 12.531
Authors: Ch Van Kesteren; R A A Mathôt; E Raymond; J P Armand; Ch Dittrich; H Dumez; H Roché; J P Droz; C Punt; M Ravic; J Wanders; J H Beijnen; P Fumoleau; J H M Schellens Journal: J Clin Oncol Date: 2002-10-01 Impact factor: 44.544
Authors: Anthe S Zandvliet; Alwin D R Huitema; William Copalu; Yasuhide Yamada; Tomohide Tamura; Jos H Beijnen; Jan H M Schellens Journal: Clin Cancer Res Date: 2007-05-15 Impact factor: 12.531
Authors: M Joerger; D Hess; A Delmonte; E Gallerani; A Fasolo; L Gianni; S Cresta; P Barbieri; S Pace; C Sessa Journal: Br J Clin Pharmacol Date: 2015-06-03 Impact factor: 4.335
Authors: J G Coen van Hasselt; Anubha Gupta; Ziad Hussein; Jos H Beijnen; Jan H M Schellens; Alwin D R Huitema Journal: Br J Clin Pharmacol Date: 2013-09 Impact factor: 4.335