Takuya Kaneko1,2, Kosuke Doki3,4, Takeshi Yamada5, Yoshiyuki Yamamoto5, Toshikazu Moriwaki5, Yoshiharu Suzuki2, Masato Homma1,2. 1. Department of Pharmacy, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan. 2. Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan. 3. Department of Pharmacy, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan. k-doki@md.tsukuba.ac.jp. 4. Department of Pharmaceutical Sciences, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai 1-1-1, Tsukuba, Ibaraki, 305-8575, Japan. k-doki@md.tsukuba.ac.jp. 5. Division of Gastroenterology, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan.
Abstract
BACKGROUND: Therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are used to treat advanced gastric cancer (AGC). Malignant ascites is often accompanied by peritoneal metastasis in AGC patients. However, the distribution of therapeutic monoclonal antibodies into ascites has yet to be adequately investigated. METHODS: We determined serum and ascites concentrations of ramucirumab or nivolumab and total IgG in three AGC patients with massive ascites. When serum and ascites samples were obtained on the same day, the ascites-to-serum ratio (A/S ratio) of the concentration of monoclonal antibodies was evaluated. The relationship between time after last infusion and the A/S ratio of therapeutic monoclonal antibodies was examined using 15 datasets from the present study and the literature. RESULTS: Ramucirumab and nivolumab were detected in massive ascites at considerable amounts (A/S ratios of 0.24-0.35 for ramucirumab and 0.17-0.55 for nivolumab). A positive correlation was detected between the A/S ratios of the therapeutic monoclonal antibodies and the time after last infusion (r = 0.747). Removal of ascites using paracentesis eliminated at least 15.3%-30.3% and 5.2-27.4% of the injected ramucirumab and nivolumab, respectively. Endogenous IgG, as well as therapeutic monoclonal antibodies, were distributed into ascites; the A/S ratios for IgG were 0.22-0.45. CONCLUSION: Our results suggest that therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are distributed into massive ascites in AGC patients concomitantly with endogenous IgG. In these patients, retention of ascites and its removal may result in decreased systemic drug exposure to ramucirumab and nivolumab.
BACKGROUND: Therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are used to treat advanced gastric cancer (AGC). Malignant ascites is often accompanied by peritoneal metastasis in AGC patients. However, the distribution of therapeutic monoclonal antibodies into ascites has yet to be adequately investigated. METHODS: We determined serum and ascites concentrations of ramucirumab or nivolumab and total IgG in three AGC patients with massive ascites. When serum and ascites samples were obtained on the same day, the ascites-to-serum ratio (A/S ratio) of the concentration of monoclonal antibodies was evaluated. The relationship between time after last infusion and the A/S ratio of therapeutic monoclonal antibodies was examined using 15 datasets from the present study and the literature. RESULTS: Ramucirumab and nivolumab were detected in massive ascites at considerable amounts (A/S ratios of 0.24-0.35 for ramucirumab and 0.17-0.55 for nivolumab). A positive correlation was detected between the A/S ratios of the therapeutic monoclonal antibodies and the time after last infusion (r = 0.747). Removal of ascites using paracentesis eliminated at least 15.3%-30.3% and 5.2-27.4% of the injected ramucirumab and nivolumab, respectively. Endogenous IgG, as well as therapeutic monoclonal antibodies, were distributed into ascites; the A/S ratios for IgG were 0.22-0.45. CONCLUSION: Our results suggest that therapeutic monoclonal antibodies, including ramucirumab and nivolumab, are distributed into massive ascites in AGC patients concomitantly with endogenous IgG. In these patients, retention of ascites and its removal may result in decreased systemic drug exposure to ramucirumab and nivolumab.
Authors: M Tahara; A Ohtsu; N Boku; F Nagashima; M Muto; Y Sano; M Yoshida; K Mera; S Hironaka; H Tajiri; S Yoshida Journal: Gastric Cancer Date: 2001 Impact factor: 7.370
Authors: B J Delauter; R K Ramanathan; M J Egorin; L L Stover; E G Zuhowski; W Plunkett; W C Zamboni Journal: Pharmacotherapy Date: 2000-10 Impact factor: 4.705
Authors: Jennifer L Spratlin; Roger B Cohen; Matthew Eadens; Lia Gore; D Ross Camidge; Sami Diab; Stephen Leong; Cindy O'Bryant; Laura Q M Chow; Natalie J Serkova; Neal J Meropol; Nancy L Lewis; E Gabriela Chiorean; Floyd Fox; Hagop Youssoufian; Eric K Rowinsky; S Gail Eckhardt Journal: J Clin Oncol Date: 2010-01-04 Impact factor: 44.544