Personalising docetaxel and G-CSF schedules in cancer patients by a clinically validated computational model

Abstract

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.

Figure 1

Schematic description of the combined docetaxel/granulopoiesis model. Docetaxel (upper box) is represented by a three-compartment PK model, arrows represent exchange constants of the drug between the central and peripheral compartments (k₁₂, k₂₁, k₁₃, k₃₁) and the elimination rate from the body (k_el). Granulopoiesis (lower box) is described as a pipeline initiated by myeloid progenitors (including colony forming unit of granulocyte, erythrocyte, monocyte and megakaryocyte; CFU of granulocyte and monocyte; and CFU of granulocyte) inflowing to the myeloblasts compartment, then, sequentially, differentiating into promyelocytes, myelocytes, post-mitotic (PM) BM cells, and finally being released to blood as mature neutrophils (NEUs). G-CSF accelerates proliferation, transition through the mitotic compartment, release of post-mitotic cells to blood and their apoptosis. Docetaxel targets cells in the mitotic compartments.

Figure 2

The model’s predictions compared with clinical outcomes. An example of model-predicted neutrophil counts over time (solid lines) compared with the observed neutrophil counts (empty circles) of four MBC patients treated with different docetaxel schedules: (A) 25–35 mg m⁻² once weekly; (B–D) 100–75 mg m⁻² tri-weekly; (E) nadir days at each cycle, of patients receiving tri-weekly docetaxel (circles), model’s predictions (abscissa), clinical observations (ordinate) and identity line (dashed line; here, the dashed line cannot be seen as it converges with the correlation line); N=66. Calculated correlation coefficient, r=0.99.

Figure 3

Neutrophils as a function of the docetaxel/G-CSF regimen. Treatment of MBC patients by G-CSF following a single administration of docetaxel was simulated using the population-adjusted physiological model. (A) Simulation results of blood neutrophil counts over time, following standard docetaxel administration of 100 mg m⁻² tri-weekly; docetaxel only – no G-CSF (dashed–dotted line); standard G-CSF regimen: 300 μg per day, QD × 5, starting 1 day after docetaxel (dotted line) or improved G-CSF regimen: 150 μg per day, QD × 3, starting on day 7 (solid line); upper limits of grades 3 and 4 neutropenia appear as black horizontal long and short dashed lines, respectively. (B) Simulation results of blood neutrophil counts over time, following dose intense (not approved) docetaxel administration of 150 mg m⁻² tri-weekly; docetaxel only – no G-CSF (dashed–dotted line); standard G-CSF regimen 300 μg per day, QD × 5, starting 1 day after docetaxel (dotted line) or improved G-CSF regimen: 300 μg per day, QD × 4, starting on day 5 (solid line); upper limits of grades 3 and 4 neutropenia appear as described in A.

Figure 4

Optimisation of G-CSF regimen in an average patient (initial counts: 4250 neutrophils per μl) treated by Doc; grade 3 neutropenia as a function of G-CSF administration regimen. (A) Doc 100 mg m⁻² G-CSF onset on day 7; (B) Doc 100 mg m⁻² G-CSF onset on day 5; (C) Doc 150 mg m⁻² G-CSF onset on day 7; (D) Doc 150 mg m⁻² G-CSF onset on day 5. The number of daily G-CSF dosings appears in the window.The optimal G-CSG regimens, minimising both neutropenia and cost for Doc 100 and 150 mg m⁻² are G-CSF 300 μg per day, Q1D × 3, on day 7 (A) and G-CSF 300 μg per day, Q1D × 4, on day 5 (D), respectively.