Relationship between cytochrome 3A activity, inflammatory status and the risk of docetaxel-induced febrile neutropenia: a prospective study

Background: We hypothesized that cancer-related inflammation might increase the risk of febrile neutropenia (FN) induced by docetaxel (DCX, Taxotere), by both affecting the exposure to DCX and the tissue sensitivity. Patients and methods: Advanced cancer patients with normal liver function, performance status (PS) < 3, were included. Cytochrome P450 3A (CYP 3A) activity was estimated before the first cycle of DCX by a single determination of midazolam plasma concentration, 4 hours after 0.015 mg/kg i.v. bolus. Following the first cycle of 75-100 mg/m(2) DCX, clearance and area under the concentration versus time curve (AUC) were estimated using a limited sampling strategy. Results: Among 56 assessable patients, 7 FNs occurred after first cycle (13%). In univariate analysis, high midazolam concentration and free DCX AUC were associated with severe neutropenia and FN. In addition to DCX exposure-related parameters, the risk of FN was also correlated with poor PS, baseline lymphopenia and lung cancer, while high ferritin level, indicator of an inflammatory state, reached borderline significance (P = 0.07). By multivariate analysis, total DCX AUC and baseline lymphopenia were associated with FN. High midazolam concentration was correlated with elevated ferritin level (r = 0.32; P = 0.02). Conclusion: Inflammatory status and lymphocyte count should be included in the evaluation of the benefice/risk ratio before the initiation of DCX.