Covariate-based dose individualization of the cytotoxic drug indisulam to reduce the risk of severe myelosuppression.
OBJECTIVE
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.
Zandvliet
Anthe S
AS
Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands.
Schellens
Jan H M
JH
Copalu
William
W
Beijnen
Jos H
JH
Huitema
Alwin D R
AD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000465:Algorithms; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001830:Body Surface Area; D002986:Clinical Trials as Topic; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D003603:Cytotoxins / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000517:prevention & control*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D009503:Neutropenia / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D044469:Racial Groups; D012306:Risk; D012307:Risk Factors; D012737:Sex Factors; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced / Q000175:diagnosis / Q000517:prevention & control; D055815:Young Adult
D000970:Antineoplastic Agents; D003603:Cytotoxins; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System