Kenji Ikemura1, Kosuke Oshima2, Tomoyuki Enokiya1, Akiharu Okamoto1, Hiroyasu Oda3, Toshiro Mizuno3, Hajime Ishinaga4, Yuichi Muraki1, Takuya Iwamoto1, Kazuhiko Takeuchi4, Naoyuki Katayama3, Masahiro Okuda5. 1. Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. 2. Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, 513-8670, Japan. 3. Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan. 4. Department of Otorhinolaryngology-Head and Neck Surgery, Mie University Graduate School of Medicine, Tsu, Mie, 514-8507, Japan. 5. Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan. okudam@clin.medic.mie-u.ac.jp.
Abstract
PURPOSE: The nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP-induced nephrotoxicity. METHODS: We analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury. RESULTS: The rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan-Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033). CONCLUSIONS: These findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy.
PURPOSE: The nephrotoxicity of cisplatin (CDDP) is its dose-limiting side effect, and is caused by renal accumulation of CDDP mainly via organic cation transporter 2 (OCT2). Because proton pump inhibitors (PPIs) are known to inhibit OCT2 activity, PPI might ameliorate CDDP-induced nephrotoxicity. In the present study, we retrospectively investigated the effect of co-administration of PPI on CDDP-induced nephrotoxicity. METHODS: We analyzed the impact of PPI on the development of nephrotoxicity in 133 patients who received CDDP and fluorouracil (5-FU) therapy for the treatment of esophageal cancer or head and neck cancer. Nephrotoxicity that developed within 14 days following CDDP administration was evaluated in accordance with Common Terminology Criteria for Adverse Events ver. 4.0 for acute kidney injury. RESULTS: The rate of nephrotoxicity in patients with PPI (12%, n = 33) was significantly lower than that in patients without PPI (30%, n = 100). Severe nephrotoxicity greater than Grade 2 was not observed in patients with PPI, whereas the rate of hematological toxicity was comparable between patients with and without PPI. Kaplan-Meier analysis showed that the time to nephrotoxicity following CDDP administration was significantly prolonged in patients with PPI. Multivariate analysis revealed that co-administration of PPI with CDDP and 5-FU was an independent factor significantly contributing to the amelioration of nephrotoxicity (odds ratio 0.239, p = 0.033). CONCLUSIONS: These findings indicate that co-administration of clinical doses of PPI could ameliorate nephrotoxicity without exacerbation of hematological toxicity in patients receiving CDDP and 5-FU therapy.
Authors: Alfredo G Casanova; María Teresa Hernández-Sánchez; Francisco J López-Hernández; Carlos Martínez-Salgado; Marta Prieto; Laura Vicente-Vicente; Ana Isabel Morales Journal: Eur J Clin Pharmacol Date: 2019-11-01 Impact factor: 2.953