PK/PD model of indisulam and capecitabine: interaction causes excessive myelosuppression.

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Zandvliet AS, Siegel-Lakhai WS, Beijnen JH, Copalu W, Etienne-Grimaldi MC, Milano G, Schellens JH, Huitema AD

PK/PD model of indisulam and capecitabine: interaction causes excessive myelosuppression.

Clin Pharmacol Ther. 2008 Jun;83(6):829-39. Epub 2007 Sep 12.

PubMed ID

17851564 [ View in PubMed

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Abstract

The anticancer agent indisulam was evaluated in a dose-escalation study in combination with capecitabine. Severe myelotoxicity was observed after multiple treatment cycles. We hypothesized that capecitabine inhibits the synthesis of CYP2C9, which metabolizes indisulam. The objectives were to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the combination treatment and to estimate the impact of a drug-drug interaction on the safety of various dose levels. NONMEM was used to develop a PK/PD model, including the impact of capecitabine coadministration on indisulam pharmacokinetics. A simulation study was performed to evaluate the risk of dose-limiting neutropenia. A time-dependent pharmacokinetic drug-drug interaction resulted in increased exposure to indisulam and in increased myelotoxicity. The risk of dose-limiting neutropenia increased with treatment duration and with dose. The excessive myelosuppression after multiple cycles may be explained by a pharmacokinetic interaction between indisulam and capecitabine. The combination of 550 mg/m(2) indisulam and 1,250 mg/m(2) capecitabine twice daily was considered safe.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Indisulam	Cytochrome P450 2C9	Protein	Humans	Unknown	Substrate	Details