Impact of gene polymorphisms on the systemic toxicity to paclitaxel/carboplatin chemotherapy for treatment of gynecologic cancers.

PURPOSE: Gynecologic malignancies are often detected in advanced stages, requiring chemotherapy with taxane/platinum combinations, which may cause severe toxicities, such as neutropenia and peripheral neuropathy. Gene polymorphisms are suspected as possible causes for the interindividual variability on chemotherapy toxicities. OBJECTIVE: To evaluate the role of ABCB1 1236C>T, 3435C>T; CYP2C8*3; CYP3A5*3C variants on paclitaxel/carboplatin toxicities. METHODS: A cohort of 503 gynecologic cancer patients treated with paclitaxel/carboplatin at the Brazilian National Cancer Institute (INCA-Brazil) was recruited (2013-2017). Polymorphisms were genotyped by real-time PCR, and toxicities were evaluated by patients' interviews at each chemotherapy cycle and by data collection from electronic records. The association of clinical features and genotypes with severe toxicities was estimated using Pearson's Chi square tests and multiple regression analyses, with calculation of adjusted odds ratios (ORadjusted), and respective 95% confidence intervals (95% CI). RESULTS: CYP2C8*3 was significantly associated with increased risks of severe (grades 3-4) neutropenia (ORadjusted 2.11; 95% CI 1.24-3.6; dominant model) and severe thrombocytopenia (ORadjusted 4.93; 95% CI 1.69-14.35; recessive model), whereas ABCB1 variant genotypes (ORadjusted 2.13; 95% CI 1.32-3.42), in association with CYP2C8*3 wild type (GG) (ORadjusted 1.93; 95% CI 1.17-3.19), were predictive of severe fatigue. CONCLUSIONS: The present study suggests that CYP2C8*3 is a potential predictor of hematological toxicities related to paclitaxel/carboplatin treatment. Since hematological toxicities, especially neutropenia, may lead to dose delay or treatment interruption, such prognostic evaluation may contribute to clinical management of selected patients with paclitaxel-based chemotherapy.

A Rapid and Simple HPLC Method for Therapeutic Monitoring of Vancomycin.

Therapeutic monitoring of the antibiotic vancomycin is important to achieve specific plasma concentration and prevent toxic effects. Several assays have been described for vancomycin determination in clinical practice, but high-performance liquid chromatography is still considered the gold standard for the quantification of vancomycin. In this study, we developed a new and rapid high-performance liquid chromatography method requiring 50 µL of plasma for the quantification of vancomycin. Acetonitrile was used for processing plasma by protein precipitation (1:2.5). Isocratic chromatographic analysis was carried out on a C18 silica-based (2.7 µm) column with the mobile phase containing 20 mM ammonium acetate/formic acid buffer (pH 4.0):methanol 88:12 (v/v). A diode array detector was used for UV detection at 240 nm. This method was validated according to the Brazilian Health Surveillance Agency legislation and International Conference on Harmonization guidelines. The measurement range was 1-100 µg/mL, analysis time was 8 min, and intermediate precision was <12%, supporting the present method as a fast, simple, and effective alternative for therapeutic monitoring of vancomycin.