Lack of pharmacokinetic drug-drug interaction between ramucirumab and paclitaxel in a phase II study of patients with advanced malignant solid tumors.

Laura Q M Chow,Antoinette R Tan,Dale R Shepard,Ding Wang,Archana Chaudhary,David C Smith,Ling Gao,Yong Lin,Crystal S Denlinger

doi:10.1007/s00280-016-3098-3

Abstract

PurposeThe objective of this phase II study was to evaluate pharmacokinetic interaction potential between ramucirumab and paclitaxel in patients with advanced cancer.MethodsThis study was designed to assess 2-way pharmacokinetic drug–drug interactions between ramucirumab and paclitaxel. Twenty-four patients participated in Part A, which consisted of a 2-week monotherapy period in which paclitaxel 80 mg/m2 was administered on day 1, followed by a 4-week cycle of combination treatment with ramucirumab (8 mg/kg on days 1 and 15; paclitaxel on days 1, 8, and 15). Patients could continue to receive combination therapy with ramucirumab and paclitaxel. In 16 patients in Part B, ramucirumab monotherapy was administered on day 1 of a 3-week cycle. Patients could continue to receive ramucirumab monotherapy or combination therapy with paclitaxel.ResultsConcomitant administration of ramucirumab had no effect on pharmacokinetics of paclitaxel, with ratios of geometric least squares (LS) means (with ramucirumab vs. alone) of 1.09 (90 % confidence interval [CI] 0.93, 1.29) for AUC(0–∞) and 0.97 (90 % CI 0.83, 1.13) for Cmax. In addition, similar ramucirumab pharmacokinetic characteristics were observed with or without paclitaxel administration. The ratios of geometric LS means of AUC(0–∞) and Cmax of ramucirumab (with paclitaxel vs. alone) were 1.00 (90 % CI 0.84, 1.19) for AUC(0–∞) and 1.07 (90 % CI 0.93, 1.24) for Cmax, respectively.ConclusionsConcomitant paclitaxel administration is unlikely to affect the pharmacokinetics of ramucirumab, and vice versa. The incidence and severity of adverse events were consistent with the known safety profiles of paclitaxel and ramucirumab.

Highlights

USA 4 Fox Chase Cancer Center, Philadelphia, PA, USA 5 Henry Ford Hospital, Detroit, MI, USA 6 Cleveland Clinic Foundation, Cleveland, OH, USA 7 Eli Lilly and Company, Indianapolis, IN, USA 8 Eli Lilly and Company, Bridgewater, NJ, USAPathways that mediate angiogenesis are considered important targets in cancer drug development
Vascular endothelial growth factors (VEGFs) receptor 2 (VEGFR-2) is the primary mediator of proangiogenic effects of VEGF-A, and experimental evidence suggests that the VEGF-A/ VEGFR-2 interaction plays an important role in tumor angiogenesis, a process essential for tumor growth and metastasis [1, 2]
Ramucirumab is a recombinant human immunoglobulin G1 monoclonal antibody that binds to the VEGFR-2 receptor with high affinity, preventing binding

Summary

Introduction

USA 4 Fox Chase Cancer Center, Philadelphia, PA, USA 5 Henry Ford Hospital, Detroit, MI, USA 6 Cleveland Clinic Foundation, Cleveland, OH, USA 7 Eli Lilly and Company, Indianapolis, IN, USA 8 Eli Lilly and Company, Bridgewater, NJ, USAPathways that mediate angiogenesis are considered important targets in cancer drug development. In patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma, the results from 2 randomized, phase III trials demonstrated that overall survival was significantly increased in patients who received ramucirumab as monotherapy (hazard ratio [HR] 0.78; 95 % confidence interval [CI] 0.60, 0.998; P = 0.047) and in combination with paclitaxel (HR 0.81; 95 % CI 0.68, 0.96; P = 0.017) [5, 6]. These trials led to approval of ramucirumab as second-line therapy for advanced gastric cancer

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