Investigating the clinical impact of dose-banding for weekly paclitaxel in patients with breast cancer: A retrospective and monocentric study.

AIMS: Dose-banding (DB) consists in approximating the theoretical dose of anticancer drugs calculated according to the body surface area (Dose-BSA) of patients. This concept is supported by pharmacokinetic but not by clinical data. The aim of this study was to assess the clinical outcome of DB defined as dose-fitting up to ±10%. METHODS: This was a retrospective study conducted in patients receiving weekly paclitaxel in neoadjuvant (NAT) and metastatic (M+) settings. Three groups of patients were considered according to type of paclitaxel dosing: Dose-BSA, DB approximated down (DB-Low) and DB approximated up (DB-High). Efficacy was evaluated by the rate of pathological complete response for patients in NAT setting and by the median of progression-free survival plus overall survival for those in M+ setting. Toxicity and efficacy were compared in the 3 groups. RESULTS: A total of 224 and 209 patients were assessable in the M+ and NAT settings, respectively. A toxic event was observed for 31.7 and 27.3% in M+ and NAT, respectively. The rate of pathological complete response was 41.6% in NAT. The median progression-free survival was 5.2 (4.1-5.8) months and overall survival was 16.3 (14.6-18.4) months for patients in M+. Efficacy and toxicity were not different in DB-Low and DB-High groups compared to Dose-BSA group. CONCLUSION: DB with approximated doses up to ±10% does not seem to influence clinical outcome of patients treated with weekly paclitaxel. This is the first study to include clinical observations, which lends support to DB as a safe and effective dosing method.

Association between clinically relevant toxicities of pazopanib and sunitinib and the use of weak CYP3A4 and P-gp inhibitors.

PURPOSE: Sunitinib and pazopanib, two tyrosine kinase inhibitors (TKI), may be targets of potential pharmacokinetic drug-drug interactions (P-PK-DDIs). While strong cytochrome P4503A (CYP3A4) inhibitors or inducers should cause a clinically relevant modification in plasma TKI concentrations, the effect of weak inhibitors is unknown. The objective of this study was to evaluate the association between weak P-PK-DDI and clinically relevant toxicity in real life. PATIENTS AND METHODS: This was a single-center retrospective study including patients treated with sunitinib or pazopanib for any malignancies, for whom a PK-DDI analysis was performed before starting TKI. The primary endpoint was the correlation between P-PK-DDIs and a dose decrease after 1 month of treatment. The secondary endpoint was the correlation between PK-DDIs and drug withdrawal due to toxicity. RESULTS: Seventy-six patients were assessed. A P-PK-DDI with weak CYP3A4 or P-gp inhibition was found in 14 patients. In patients with P-PK-DDI or without, the dose was reduced during the first month in 57.1% and 17.7% (p = 0.003) and the drug withdrawn in 42.8% and 11.3% (p = 0.011), respectively. In multivariate analysis, a significant correlation was found between P-PK-DDI (CYP3A4 and P-gp inhibitors) and dose reduction, and between drug withdrawal and PK-DDI (CYP3A4 inhibitors). CONCLUSION: P-PK-DDI was correlated with dose reduction and drug withdrawal due to toxicity. The causality of this relationship warrants to be assessed; therefore, therapeutic drug monitoring is necessary in patients treated with TKI.