Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model.
BACKGROUND
This study was aimed to develop a new method for personalising chemotherapeutic and granulocyte colony-stimulating factor (G-CSF) combined schedules, and use it for suggesting efficacious chemotherapy with reduced neutropenia.


METHODS
Clinical data from 38 docetaxel (Doc)-treated metastatic breast cancer patients were employed for validating a new pharmacokinetic/pharmacodynamics model for Doc, combined with a mathematical model for granulopoiesis. An optimisation procedure was constructed and used for selecting improved treatment schedules.


RESULTS
The combined model accurately predicted observed nadir timing (r=0.99), grade 3 or 4 neutropenia (86% success) and neutrophil counts over time in individual patients (r=0.63), and showed robustness to CYP3A-induced variability in Doc clearance. For average patients, the predicted optimal support for the standard chemotherapy regimen, Doc 100 μg m(-2) tri-weekly, is G-CSF, 300 μg, Q1D × 3, starting day 7 post-Doc. This regimen largely moderates chemotherapy-induced neutrophil nadir and neutropenia duration. The more intensive Doc dose, 150 mg m(-2), is optimally supported by the slightly less cost-effective G-CSF 300 μg, Q1D × 4, 5 days post-Doc. The latter regimen is optimal for borderline patients (2000 neutrophils per μl) under Doc, 100-150 mg m(-2) tri-weekly.


CONCLUSIONS
The new computational method can serve for tailoring efficacious cytotoxic and supportive treatments, minimising side effects to individual patients. Prospective clinical validation is warranted.
Optimata Ltd, 7 Abba Hillel Street, Ramat-Gan 52522, Israel.
O
O
Vainas
S
S
Ariad
O
O
Amir
W
W
Mermershtain
V
V
Vainstein
M
M
Kleiman
O
O
Inbar
R
R
Ben-Av
A
A
Mukherjee
S
S
Chan
Z
Z
Agur
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003198:Computer Simulation; D000077143:Docetaxel; D004334:Drug Administration Schedule; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006098:Granulocytes / Q000166:cytology / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D009503:Neutropenia / Q000139:chemically induced / Q000188:drug therapy; D015203:Reproducibility of Results; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel