title: Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy.
abstract: Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen.
authors.affiliation: Pharmacokinetics Unit, Faculty of Pharmacy, Aix Marseille University, SMARTc, Inserm CRO2 UMR_S 911, 27, bd. Jean Moulin, CS 30064, 13385, Marseille, France.|OCP-TCO, Novartis Pharma AG, WSJ-340.5.25.27, Basel, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Meille
authors.affiliation: Pharmacokinetics Unit, Faculty of Pharmacy, Aix Marseille University, SMARTc, Inserm CRO2 UMR_S 911, 27, bd. Jean Moulin, CS 30064, 13385, Marseille, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Barbolosi
authors.affiliation: Pharmacokinetics Unit, Faculty of Pharmacy, Aix Marseille University, SMARTc, Inserm CRO2 UMR_S 911, 27, bd. Jean Moulin, CS 30064, 13385, Marseille, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.affiliation: EMR3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard, Oullins, France.|Université de Lyon, Lyon, France.|Institut de Cancérologie des HCL, Service d'Oncologie Médicale, Centre Hospitalier Lyon-Sud, Lyon, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Freyer
authors.affiliation: Pharmacokinetics Unit, Faculty of Pharmacy, Aix Marseille University, SMARTc, Inserm CRO2 UMR_S 911, 27, bd. Jean Moulin, CS 30064, 13385, Marseille, France. athanassios.iliadis@univ-amu.fr.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Iliadis
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D003131:Combined Modality Therapy / Q000379:methods*; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D008962:Models, Theoretical; D009362:Neoplasm Metastasis; D043823:Taxoids / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D015251:Epirubicin