临床药理学与生物药剂学

抽象的

Phase II Study Evaluating the Effect of Concomitant Ramucirumab on the Pharmacokinetics of Docetaxel in Patients with Advanced Solid Tumors

Mark N Stein*, Laura Q M Chow, David C Smith, Dale R Shepard, Ding Wan, John Powderly, Archana Chaudhary, Yong Lin and Ling Gao

Background: Ramucirumab is a human IgG1 monoclonal antibody that specifically targets the vascular endothelial growth factor receptor-2. The primary objective of this study was to investigate the effect of concomitant ramucirumab on the pharmacokinetics of docetaxel. Methods: Patients with metastatic or locally advanced malignant solid tumors resistant to standard therapy or for which no standard therapy was available were recruited. Patients received docetaxel 75 mg/m2 and ramucirumab 10 mg/kg on day 1 of a 3-week cycle. In cycle 1, docetaxel was administered alone; in cycle 2 and subsequent cycles, ramucirumab was administered followed by docetaxel. Blood was drawn immediately before and at regular intervals after infusions for cycles 1 and 2 to determine docetaxel and ramucirumab concentrations. Results: Docetaxel pharmacokinetic parameters were assessed in 18 patients. The dose-normalized area under the plasma concentration versus time curve from time zero extrapolated to infinity and maximum plasma drug concentration of docetaxel during cycle 2 were similar to those when docetaxel was administered alone during cycle 1, with geometric least squares means ratios of 0.97 (90% CI: 0.84, 1.10) for the area under the plasma concentration versus time curve from time zero extrapolated to infinity and 1.14 (90% CI: 0.84, 1.55) for the maximum plasma drug concentration. Of the 22 patients who received any dose of study drug, the most commonly reported treatment-emergent adverse events included nausea (12 patients, 54.5%), fatigue, leukopenia, and neutropenia (each in nine patients, 40.9%). The most commonly reported grade ≥ 3 treatment-emergent adverse events were leukopenia and neutropenia (each in seven patients, 31.8%). Conclusions: Coadministration of ramucirumab had no effect on the pharmacokinetics of docetaxel. The incidence and severity of treatment-emergent adverse events were consistent with the known safety profiles of docetaxel and ramucirumab.