Neutrophil dynamics during concurrent chemotherapy and G-CSF administration: Mathematical modelling guides dose optimisation to minimise neutropenia.
The choice of chemotherapy regimens is often constrained by the patient's tolerance to the side effects of chemotherapeutic agents. This dose-limiting issue is a major concern in dose regimen design, which is typically focused on maximising drug benefits. Chemotherapy-induced neutropenia is one of the most prevalent toxic effects patients experience and frequently threatens the efficient use of chemotherapy. In response, granulocyte colony-stimulating factor (G-CSF) is co-administered during chemotherapy to stimulate neutrophil production, increase neutrophil counts, and hopefully avoid neutropenia. Its clinical use is, however, largely dictated by trial and error processes. Based on up-to-date knowledge and rational considerations, we develop a physiologically realistic model to mathematically characterise the neutrophil production in the bone marrow which we then integrate with pharmacokinetic and pharmacodynamic (PKPD) models of a chemotherapeutic agent and an exogenous form of G-CSF (recombinant human G-CSF, or rhG-CSF). In this work, model parameters represent the average values for a general patient and are extracted from the literature or estimated from available data. The dose effect predicted by the model is confirmed through previously published data. Using our model, we were able to determine clinically relevant dosing regimens that advantageously reduce the number of rhG-CSF administrations compared to original studies while significantly improving the neutropenia status. More particularly, we determine that it could be beneficial to delay the first administration of rhG-CSF to day seven post-chemotherapy and reduce the number of administrations from ten to three or four for a patient undergoing 14-day periodic chemotherapy.
Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada H3C 3J7; Centre for Applied Mathematics in Bioscience and Medicine (CAMBAM), McGill University, Montreal, QC, Canada H3G 1Y6. Electronic address: morgan.craig@umontreal.ca.
Morgan
M
Craig
Department of Mathematics and Statistics, McGill University, Montreal, QC, Canada H3A 0B9; Centre for Applied Mathematics in Bioscience and Medicine (CAMBAM), McGill University, Montreal, QC, Canada H3G 1Y6; Centre de recherches mathématiques, Université de Montréal, Montréal, QC, Canada H3C 3J7. Electronic address: tony.humphries@mcgill.ca.
Antony R
AR
Humphries
Centre for Applied Mathematics in Bioscience and Medicine (CAMBAM), McGill University, Montreal, QC, Canada H3G 1Y6; Centre de recherches mathématiques, Université de Montréal, Montréal, QC, Canada H3C 3J7. Electronic address: fahima.nekka@umontreal.ca.
Fahima
F
Nekka
Département de mathématiques et de statistique, Université de Montréal, Montréal, QC, Canada H3C 3J7; Centre for Applied Mathematics in Bioscience and Medicine (CAMBAM), McGill University, Montreal, QC, Canada H3G 1Y6; Centre de recherches mathématiques, Université de Montréal, Montréal, QC, Canada H3C 3J7. Electronic address: jacques.belair@umontreal.ca.
Jacques
J
Bélair
Faculté de Pharmacie, Université de Montréal, Montréal, QC, Canada H3C 3J7; Centre for Applied Mathematics in Bioscience and Medicine (CAMBAM), McGill University, Montreal, QC, Canada H3G 1Y6; Centre de recherches mathématiques, Université de Montréal, Montréal, QC, Canada H3C 3J7. Electronic address: li@crm.umontreal.ca.
Jun
J
Li
Department of Mathematics and Statistics, McGill University, Montreal, QC, Canada H3A 0B9; Centre for Applied Mathematics in Bioscience and Medicine (CAMBAM), McGill University, Montreal, QC, Canada H3G 1Y6; Departments of Physiology and Physics, McGill University, Montreal, QC, Canada H3G 1Y6. Electronic address: michael.mackey@mcgill.ca.
Michael C
MC
Mackey
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D000069585:Filgrastim / Q000008:administration & dosage / Q000494:pharmacology*; D006401:Hematologic Agents / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D008954:Models, Biological; D038042:Myelopoiesis / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects*; D044005:Tetrahydroisoquinolines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006401:Hematologic Agents; C500383:PM 00104; D044005:Tetrahydroisoquinolines; D000069585:Filgrastim
Myelopoeisis; Pharmacokinetics/pharmacodynamics; Physiological mathematical modelling