Summary
Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We conducted the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1 [normal]; Category 2 [mild: ALP, AST and/or ALT≤5 ХULN, and TB within normal range]; Category 3 [moderate: any ALP, and AST or ALT≤5-10ХULN, and/or TB≤1-1.5 ХULN]. Category 1, 2 and 3 patients received starting dosages of 40mg/m2, 30mg/m2 and 20mg/m2 docetaxel respectively. Pharmacokinetics was evaluated on Day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was performed weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P<0.001). Median clearance was 22.8, 16.4 and 11.3L/h/m2 in Categories 1, 2 and 3 respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (AUC) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median AUC was 1.74, 1.83 and 1.77mg·h/L in Categories 1, 2 and 3 respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and NCI-ODWG grouping systems suggests that the proposed classification system appears to more effectively discriminate patients by docetaxel clearance and dose requirements.
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