Optimization of G-CSF dosing schedule in patients treated with eribulin: a modeling approach

• Published in: Cancer chemotherapy and pharmacology 2022-02, Vol.89 (2), p.197-208
• Main Authors: Reda, Manon, Macaire, Pauline, Bellio, Hélène, Uwer, Lionel, Ilie, Silvia, Lorgis, Véronique, Hennequin, Audrey, Ladoire, Sylvain, Rederstorff, Emilie, Fumoleau, Pierre, Isambert, Nicolas, Bonnin, Nathalie, You, Benoit, Freyer, Gilles, Desmoulins, Isabelle, Schmitt, Antonin
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Breast cancer; Breast Neoplasms - drug therapy; Cancer Research; Chemotherapy; Dosage; Drug Administration Schedule; Female; Furans - administration & dosage; Furans - adverse effects; Furans - pharmacokinetics; Granulocyte colony-stimulating factor; Granulocyte Colony-Stimulating Factor - administration & dosage; Humans; Injection; Ketones - administration & dosage; Ketones - adverse effects; Ketones - pharmacokinetics; Leukocytes (granulocytic); Leukocytes (neutrophilic); Medicine; Medicine & Public Health; Middle Aged; Models, Biological; NCT; NCT02841722; Neutropenia; Neutropenia - chemically induced; Neutropenia - prevention & control; Oncology; Optimization; Original Article; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Schedules; Structural models
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-021-04395-y

Background Granulocyte colony‐stimulating factors (G‐CSF) are commonly given to limit chemotherapy‐induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical. Objectives This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G‐CSF regimens on neutropenia’s incidence for patients treated by eribulin, to propose an optimal G‐CSF dosing schedule. Methods A population PK/PD model was developed to describe absolute neutrophil counts’ (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G‐CSF. Final model estimates were used to calculate neutropenia’s incidence following different G‐CSF dosing schedules for 1000 virtual subjects. Results The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G‐CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia. Conclusion Simulations showed a single G‐CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin‐induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence. Trial registration NCT02841722.