PAGE. Abstracts of the Annual Meeting of the Population Approach Group in Europe.
PAGE 15 (2006) Abstr 926 [www.page-meeting.org/?abstract=926]
Oral Presentation: Lewis Sheiner Student Session
Zandvliet, Anthe S. (1), Wandena S. Siegel-Lakhai (1), Jan H.M. Schellens (2,3), William Copalu (4), Gerard Milano (5), Jos H. Beijnen (1,3), Alwin D.R. Huitema (1)
(1) Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute/ Slotervaart Hospital, Amsterdam, The Netherlands; (2) Department of Medical Oncology, The Netherlands Cancer Institute/ Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; (3) Department of Biomedical Analysis, Section of Drug Toxicology, Utrecht University, Utrecht, The Netherlands; (4) Eisai Ltd., London, UK; (5) Oncopharmacology Unit, Nice, France
Introduction Indisulam is an experimental sulfonamide anticancer agent which was evaluated in a phase I dose escalation study in combination with capecitabine. Preclinical studies had demonstrated synergistic efficacy in cell lines and xenografts. Indisulam and capecitabine were administered in a treatment cycle of three weeks: a one-hour infusion of indisulam on day 1 and oral doses of capecitabine BID on days 1-14. The combination was well tolerated in the first treatment cycle, but severe side effects were observed in subsequent cycles. This suggested a time-dependent drug-drug interaction. We hypothesized that capecitabine may inhibit the synthesis of the cytochrome P450 enzyme CYP2C9, which is one of the major metabolizing enzymes of indisulam. Myelosuppression, which is a typical side effect of indisulam, was the major toxicity of the combination. Capecitabine may contribute to neutropenic and thrombocytopenic side effects by a pharmacokinetic interaction with indisulam and/or by a direct cytotoxic effect on proliferating neutrophils and thrombocytes.
Aims: The purposes of the current analysis were 1) to evaluate the role of capecitabine in the induction of hematological toxicity during combination therapy with indisulam and capecitabine in patients with colorectal cancer 2) to develop a model describing the pharmacokinetic and pharmacodynamic characteristics of the combination and 3) to apply this model to predict the severity of neutropenia at various dose levels during multiple treatment cycles.
Methods: Data from the previously published phase I dose escalation study were used to develop a population pharmacokinetic/pharmacodynamic model. The elimination of indisulam was described by a linear pathway (elimination rate constant k10) and a saturable pathway (maximal elimination rate Vmax, Michaelis Menten constant Km), either of which was tested for inhibition by capecitabine. The elimination rate constant and/or the maximal elimination rate were proportional to the amount of a hypothetical amount of CYP2C9 enzyme, which was set at 1 prior to capecitabine administration. The time profile of this enzyme was described by a transit compartment model. Capecitabine blocked the input into the first compartment during 12 hours after oral administration, which corresponds to the dosing interval of capecitabine. The number of compartments (n) was optimized and the mean transition time (MTT) from the first to the nth compartment was estimated during model development.
Results: The pharmacokinetic profile of indisulam at multiple treatment cycles was adequately described by an interaction model with an inhibitory effect of capecitabine on the saturable elimination pathway. The time-dependent effect of capecitabine was best described by a transition model with 5 compartments. The mean transition time (or turnover time) of the hypothetical CYP2C9 enzyme was 9.2 days and the variability between patients was 62%. The pharmacokinetic drug-drug interaction resulted in increased exposure to indisulam at the second and subsequent treatment cycles.
Conclusions: Co-administration of capecitabine caused a time-dependent inhibition of the saturable elimination pathway of indisulam. The pharmacokinetic interaction between indisulam and capecitabine explains the excessive hematological toxicity of the combination after multiple treatment cycles. Simulation studies have demonstrated that the risk of dose limiting neutropenia is acceptable at a dose level of indisulam 550 mg/m2 in combination with capecitabine 1250 mg/m2 BID during multiple treatment cycles.