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

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

20 Citaten (Scopus)


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/m2 capecitabine twice daily was considered safe.

Originele taal-2Engels
Pagina's (van-tot)829-839
Aantal pagina's11
TijdschriftClinical Pharmacology and Therapeutics
Nummer van het tijdschrift6
StatusGepubliceerd - jun. 2008
Extern gepubliceerdJa


Duik in de onderzoeksthema's van 'PK/PD model of indisulam and capecitabine: Interaction causes excessive myelosuppression'. Samen vormen ze een unieke vingerafdruk.

Citeer dit