A pharmacometrics model to define docetaxel target in early breast cancer. Issue 2 (28th September 2022)

• Record Type: Journal Article
• Authors: Aldaz, Azucena; Schaiquevich, Paula; Aramendía, José Manuel
• Other Names: Rieder Michael guestEditor.; Likic Robert guestEditor.
• Is Part Of: British journal of clinical pharmacology. Volume 89:Issue 2(2023)
• Page Start: 727
• Page End: 736
• Publication Date: 2022-09-28
• Subjects: breast cancer -- docetaxel -- pharmacodynamics -- pharmacokinetics -- precision medicine; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.15526
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : 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/m 2 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 (300–350 mg/m 2 ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 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 < .05). Fatigue and decrease in haemoglobin and haematocrit levels were related to docetaxel AUC and Cmax and pain to AUC. AUC and Cmax >4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour 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.