Population PK/PD Modelling & Simulation of Hematological Toxicity of Trabectedin in Cancer Subjects
Hing, Jeremy(1), Juan Jose Perez-Ruixo(1), Kim Stuyckens(1), Peter Zannikos(1), Arturo Soto-Matos(2), César Picó(2), Antoine Yver(1) and Andrew Chow(1)
(1) Johnson & Johnson Pharmaceutical Research & Development, (2) PharmaMar
Background: Neutropenia was the trabectedin (Yondelis®, ET-743) 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 trabectedin as monotherapy (dose range: 0.024 - 1.8 mg/m2) as a 1, 3 or 24 hour infusion every 21 days; 1 or 3 hour infusion on day 1, 8, 15 every 28 days; or a 1 hour 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 (ANC0), mean transit time in bone marrow (MTT), and a feedback parameter. Trabectedin 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-EMax 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 ANC0, MTT, trabectedin potency were estimated to be 4.4 x 109/L (39%), 3.99 days (40%), and 15.6 mg/L (58%), respectively. The feedback parameter, EMax 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 trabectedin 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 trabectedin were well predicted by the semi-physiological PKPD model.