A pharmacometrics model to define docetaxel target in early breast cancer
Azucena Aldaz 1 , Paula Schaiquevich 2 , José Manuel Aramendía 3 4
Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure.
Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350mg/m2 ). Docetaxel AUC and Cmax in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumor recurrence.
Results: Docetaxel clearance showed no change over the four treatment cycles but a gradual increase in the volume of distribution was observed. One third of the patients had at least one dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum, and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (p<0.05). Fatigue and decrease in hemoglobin and hematocrit levels were related to docetaxel AUC and Cmax and pain to AUC. AUC and Cmax higher than 4.5mg*h/L and 3.5mg/L, respectively, were risk factors for docetaxel toxicity while an AUC less than 4.5mg*h/L was associated with tumor recurrence.
Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.