Effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers: a population pharmacokinetic analysis.

Abstract

Considerable amounts of injected immunoglobulin G-based therapeutic monoclonal antibodies, such as ramucirumab, are distributed into ascites. This study aimed to examine the effect of massive ascites on ramucirumab pharmacokinetics in patients with gastrointestinal cancers. Population pharmacokinetic analysis of ramucirumab was performed using data on serum ramucirumab concentrations of 52 patients with gastrointestinal cancers, including 8 patients with massive ascites. The Bayesian method using the final population pharmacokinetic model was utilized to estimate trough ramucirumab concentrations after the first dose and at steady state. Population pharmacokinetic analysis revealed that massive ascites as well as body weight were influencing factors for ramucirumab clearance. The estimated ramucirumab clearance was significantly higher in patients with massive ascites than in those with no/mild ascites (0.020 ± 0.004 versus 0.013 ± 0.004 L/h, P < 0.001). The estimated trough ramucirumab concentrations were significantly lower in patients with massive ascites than in those with no/mild ascites after the first dose (26.4 ± 6.8 versus 36.1 ± 7.1μg/mL, P < 0.001) and at steady state (41.4 ± 16.3 versus 65.9 ± 18.0μg/mL, P < 0.001). In the present study, the presence of massive ascites affected the pharmacokinetics of ramucirumab in patients with gastrointestinal cancers. Our results suggest that dose optimization of ramucirumab may be necessary in patients with massive ascites due to higher ramucirumab clearance.