Carlos Pérez-Ruixo (1), Belén Valenzuela (2), José Esteban Peris (1), Pedro Bretcha-Boix (2), Vanesa Escudero-Ortiz (3), José Farré-Alegre (2), Juan José Pérez-Ruixo (4)
(1) Pharmacy and Pharmaceutical Technology Department. University of Valencia, Spain ; (2) Platform of Oncology. Hospital Quirón Torrevieja. Torrevieja, Alicante, Spain; (3) Pharmacy and Clinical Nutrition group. University CEU Cardenal Herrera, Elche, Alicante, Spain; (4) Model-Based Drug Development. Janssen Research & Development, Beerse, Belgium
Objectives: We aimed to characterize the platelet counts dynamics in peritoneal carcinomatosis patients treated with cytoreductive surgery (CRS) and quantify the effect of hyperthermic intraperitoneal oxaliplatin (HIO).
Methods: Platelet counts from 45 patients treated with CRS and HIO diluted in isotonic 4% icodextrin (cohort A), 21 patients undergoing CRS followed by HIO diluted in isotonic 5% dextrose (cohort B) and 18 patients treated with CRS without HIO (cohort C) were used to estimate the system related and drug specific parameters of a modified Harker’s cytokinetic model [1] to account for the effect of surgery and HIO on platelet dynamics. The surgery and HIO effects on the proliferation of precursor cell as well as the surgery effect in the platelets lifespan were evaluated. The effect of age, sex, body surface area, total proteins, HIO carrier solution and splenectomy on model parameters was explored. Model evaluation and simulations were undertaken to evaluate the effect of the dose, treatment duration, and significant covariates on the incidence of severe thrombocytopenia and subsequent thrombocytosis.
Results: The time course of platelet counts was well characterized by the model developed, which simultaneously accounts for the acute-immediate thrombocytopenia response induced by the CRS and the HIO effect in bone marrow, as well as the subsequent thrombocytosis due to the natural defense mechanism to prevent mayor bleedings [2]. The model evaluation evidenced an accurate prediction of the time course of platelet counts and its associated variability, as well as the incidence of severe thrombocytopenia and thrombocytosis. Age, sex, body surface area, total proteins and HIO carrier solution were not associated with the model parameters. Simulations indicated that i) both thrombocytopenia and thrombocytosis were reversible and short-lasting, ii) the severity of the thrombocytopenia is inversely correlated with the thrombocytosis severity, iii) splenectomized patients have thrombocytopenia of lower severity and thrombocytosis of higher severity, relative to a non-splenectomized patients, and iv) the HIO dose and treatment duration were the main determinants of the severity and duration of the thrombocytopenia.
Conclusions: This model suggests that thrombocytopenia is the HIO primary dose limiting toxicity. Relative to the HIO dosing regimens used up to date, higher HIO dose or longer duration of HIO treatment could be used to treat peritoneal carcinomatosis patients, without substantially increasing the risk of major haematological toxicity.
References:
[1] Harker LA, Roskos LK, Marzec UM, et al. Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers. Blood. 2000; 95: 2514-22.
[2] Folman CC, Ooms M, Kuenen B B, et al. The role of thrombopoietin in post-operative thrombocytosis. Br J Haematol. 2001;114:126-33.
Reference: PAGE 24 () Abstr 3383 [www.page-meeting.org/?abstract=3383]
Poster: Drug/Disease modeling - Oncology