The shape of the myelosuppression time profile is related to the probability of developing neutropenic fever in patients with docetaxel-induced grade IV neutropenia.

PURPOSE: Chemotherapy-induced neutropenia is associated with the risk of developing febrile neutropenia (FN). The aim was to describe the time course of myelosuppression in breast cancer patients treated with docetaxel and to investigate how the shape of the predicted myelosuppression time course and earlier proposed risk factors influence the probability of developing FN. METHODS: Neutrophil counts from 140 breast cancer patients with observed grade IV neutropenia during the first course of docetaxel treatment were included. Twenty-six of the patients (19%) experienced FN. The myelosuppression time course was described using a semi-mechanistic myelosuppression model in NONMEM. The individual myelosuppression model parameters [baseline neutrophil count, mean transit time (MTT) and drug effect parameter (EC(50))], myelosuppression descriptors (nadir, duration of grade IV neutropenia) and earlier suggested risk factors (age, performance status, haemoglobin and liver function) were explored to be related to FN by logistic regression. RESULTS: The neutrophil time course following docetaxel treatment was well described by the model. EC(50) and MTT were both significantly related to the probability of developing FN where low parameter values result in a rapid decline, low nadir and an increased risk of FN. None of the evaluated risk factors or myelosuppression descriptors were significant. CONCLUSION: The probability to develop FN in patients who experience grade IV neutropenia was dependent on the myelosuppression time profile. Patients with a rapid neutrophil decline and high drug sensitivity had a higher probability to develop FN. Model-based parameter estimates were superior predictors over descriptive values such as the nadir or duration of neutropenia.

Limited inter-occasion variability in relation to inter-individual variability in chemotherapy-induced myelosuppression.

PURPOSE: A previously developed semi-physiological model of chemotherapy-induced myelosuppression has shown consistent system-related parameter and inter-individual variability (IIV) estimates across drugs. A requirement for dose individualization to be useful is relatively low variability between treatment courses (inter-occasion variability [IOV]) in relation to IIV. The objective of this study was to evaluate and compare magnitudes of IOV and IIV in myelosuppression model parameters across six different anti-cancer drug treatments. METHODS: Neutrophil counts from several treatment courses following therapy with docetaxel, paclitaxel, epirubicin-docetaxel, 5-fluorouracil-epirubicin-cyclophosphamide, topotecan, and etoposide were included in the analysis. The myelosuppression model was fitted to the data using NONMEM VI. IOV in the model parameters baseline neutrophil counts (ANC0), mean transit time through the non-mitotic maturation chain (mean transit time [MTT]), and the parameter describing the concentration-effect relationship (slope), were evaluated for statistical significance (P < 0.001). RESULTS: Inter-occasion variability in MTT was significant for all the investigated datasets, except for topotecan, and was of similar magnitude (8-16 CV%). IOV in slope was significant for docetaxel, topotecan, and etoposide (19-39 CV%). For all six investigated datasets, the IOV in myelosuppression parameters was lower than the IIV. There was no indication of systematic shifts in the system- or drug sensitivity-related parameters over time across datasets. CONCLUSION: This study indicates that the semi-physiological model of chemotherapy-induced myelosuppression has potential to be used for prediction of the time-course of myelosuppression in future courses and is, thereby, a valuable step towards individually tailored anticancer drug therapy.