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• W2245054812 abstract "9575 Background: Neutropenia was the trabectedin (T) dose limiting toxicity in phase I studies. The objective of the present study was to develop a semi-physiological PKPD model that describes the time course of the absolute neutrophil counts (ANC) in cancer subjects receiving trabectedin. Methods: A total of 704 subjects receiving intravenous T as monotherapy (dose range: 0.024 - 1.8 mg/m 2 ) as a 1, 3 or 24 hr infusion every 21 days; 1 or 3 hr infusion on day 1, 8, 15 every 28 days; or a 1 hr infusion daily for 5 consecutive days every 21 days were used to develop (N=405, ANC=7253) and validate (N=299, ANC=4977) the model. The model comprised of a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (ANC 0 ), mean transit time in bone marrow (MTT), and a feedback parameter. T concentrations at the effect compartment were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to a sigmoid-E Max function. Model evaluation was examined using goodness of fit plots, relative error measurements, and posterior predictive checks. Computer simulations were undertaken to evaluate the neutropenia schedule dependency. Results: The mean (between subject variability, %) of the ANC 0 , MTT, T potency were estimated to be 4.4 × 10 9 /L (39%), 3.99 days (40%), and 15.6 μg/L (58%), respectively. The feedback parameter, E Max and Hill coefficient were estimated to be 0.198, 154 and 1.48. Model validation procedure evidenced accurate prediction of the incidence of grade 3/4 neutropenia. Simulations indicated that T dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model predicted time course of the ANC confirmed that neutropenia is reversible, short-lasting, and non-cumulative. Conclusions: The extent and time course of neutropenia following five different dosing regimens of T were well predicted by the semi-physiological PKPD model. [Table: see text]" @default.
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• W2245054812 date "2006-06-20" @default.
• W2245054812 modified "2023-10-18" @default.
• W2245054812 title "Semi-physiological pharmacokinetic/pharmacodynamic (PKPD) model for trabectedin-induced neutropenia" @default.
• W2245054812 doi "https://doi.org/10.1200/jco.2006.24.18_suppl.9575" @default.
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