Dose individualization of indisulam to reduce the risk of severe myelosuppression
Anthe S. Zandvliet (1), Jan H.M. Schellens (2,3), William Copalu (4), Jantien Wanders (4), Jos H. Beijnen (1,2), Alwin D.R. Huitema (1)
1 Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands, 2 Department of Biomedical Analysis, Section of Drug Toxicology, Utrecht University, Utrecht, The Netherlands, 3 Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands and 4 Eisai Ltd., London, UK
Objectives: Chemotherapy with indisulam often causes hematological toxicity. The objective of this study was to evaluate the influence of patient characteristics on the pharmacokinetics and pharmacodynamics of indisulam and to identify patients at risk for developing severe neutropenia or thrombocytopenia after treatment with indisulam.
Methods: Semi-physiological models of indisulam pharmacokinetics and hematological toxicity were used for the covariate analysis.[1,2] Concentrations of indisulam, cell counts of neutrophils and thrombocytes and patient characteristics (demographics, physical condition, prior medication, prior radiotherapy, concomitant medication, CYP2C genotype and biochemistry) of 13 clinical studies including 412 patients were used. Relationships between patient characteristics and pharmacokinetic and pharmacodynamic parameters were evaluated with the population approach using NONMEM. A simulation study was performed to determine the relative risk of dose limiting myelosuppression for the 2.5 and 97.5 percentiles of each patient characteristic. A relative risk of less than 0.9 or more than 1.1 was considered clinically relevant. A dosing algorithm was developed to assist in dose individualization.
Results: Body surface area (BSA), race and CYP2C genotype had a significant impact on indisulam elimination.(p<0.001) High body weight was related to low specific binding of indisulam in body tissue.(p<0.001) Patients who had received prior courses of chemotherapy were more sensitive to indisulam-induced neutropenia (p<0.001), but this did not result in a clinically relevant increase in the risk of dose limiting myelosuppression (relative risk (RR) 1.05). Low BSA, Japanese race, variant CYP2C genotype, low baseline neutrophil and thrombocyte counts and female sex were clinically relevant risk factors of dose limiting haematological toxicity (RR>1.1). A dosing strategy based on BSA, race, CYP2C genotype, baseline neutrophil count and sex was developed which may reduce the risk of dose limiting myelosuppression for patient subgroups.
Conclusions: This study has identified patient characteristics related to an increased risk of haematological adverse effects after therapy with indisulam. Dose individualization based on these patient characteristics may contribute to treatment optimization.
References:
[1] Zandvliet AS et al. J Pharmacokin Pharmacodyn 2006; 33: 543-70
[2] Friberg LE et al. J Clin Oncol 2002; 20: 4713-21
