Population pharmacokinetic and pharmacodynamic analysis to support treatment optimization of combination chemotherapy with indisulam and carboplatin.
OBJECTIVE
Indisulam and carboplatin have shown synergistic activity in preclinical studies. In a dose escalation study of the combination, a treatment delay was frequently required in a 3-weekly regimen to allow recovery from myelosuppression from previous cycles. A 4-weekly regimen was better tolerated, but had a decreased dose-intensity which may compromise efficacy. The aims of this study were (i) to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to describe the myelosuppressive effect of the combination, and (ii) to use this model to select a dosing regimen for Phase II evaluation.


METHODS
Sixteen patients were treated at four different dose levels of indisulam (1-h infusion on day 1) and carboplatin (30-min infusion on day 2). Pharmacokinetic data were analysed with nonlinear mixed effects modelling. A semiphysiological model describing chemotherapy-induced myelosuppression characterized the relationship between the pharmacokinetics and the haematological toxicity of indisulam and carboplatin. A simulation study was performed to evaluate the tolerability and dose-intensity for 3-weekly and 4-weekly treatment regimens.


RESULTS
The PK-PD model described the pharmacokinetics and the myelosuppressive effect of indisulam and carboplatin. The risk of a treatment delay at cycle 2 due to myelosuppression was unacceptably high (34-65%) in a 3-weekly regimen for various dose levels (350-600 mg m(-2) indisulam in combination with carboplatin to achieve an AUC of 4-6 mg min(-1) ml(-1)). This risk was acceptable for a 4-weekly regimen (9-24%), which is in line with the clinical study results.


CONCLUSIONS
This PK-PD study supports the selection of indisulam 500 mg m(-2) and a dose of carboplatin to achieve an AUC of 6 mg min(-1) ml(-1) in a 4-weekly regimen as the recommended dose for future studies.
Zandvliet
Anthe S
AS
Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. anthe.zandvliet@siz.nl
Schellens
Jan H M
JH
Dittrich
Christian
C
Wanders
Jantien
J
Beijnen
Jos H
JH
Huitema
Alwin D R
AD
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016190:Carboplatin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013921:Thrombocytopenia / Q000139:chemically induced / Q000517:prevention & control; D016896:Treatment Outcome
C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D013449:Sulfonamides; D016190:Carboplatin