Related Experiment Video
Updated: Jul 11, 2026

Modeling Chemotherapy Resistant Leukemia In Vitro
Published on: February 9, 2016
PK/PD model of indisulam and capecitabine: interaction causes excessive myelosuppression
A S Zandvliet1, W S Siegel-Lakhai, J H Beijnen
1Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands. anthe.zandvliet@slz.nl
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.
Related Concept Videos
Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
Impact of Pharmacokinetic–Pharmacodynamic Models: Regulatory Decisions
Inhibition of Cdk Activity
Drug toxicity: Drug–Drug Interaction
Pharmacokinetic–Pharmacodynamic Relationship: Model Components
Drugs that Destabilize Microtubules