1839 EVALUATING THE ASSOCIATION AMONG THE PHARMACOKINETICS OF SUNITINIB, ITS ADVERSE EVENTS AND THE TREATMENT OUTCOMES IN ADVANCED RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Advanced (I)1 Apr 20131839 EVALUATING THE ASSOCIATION AMONG THE PHARMACOKINETICS OF SUNITINIB, ITS ADVERSE EVENTS AND THE TREATMENT OUTCOMES IN ADVANCED RENAL CELL CARCINOMA Norihiko Tsuchiya, Nobuhiro Fujiyama, Shintaro Narita, Takamitsu Inoue, Kazuyuki Numakura, Susumu Akihama, Mitsuru Saito, Shigeru Satoh, Masatomo Miura, and Tomonori Habuchi Norihiko TsuchiyaNorihiko Tsuchiya Aktia, Japan More articles by this author , Nobuhiro FujiyamaNobuhiro Fujiyama Aktia, Japan More articles by this author , Shintaro NaritaShintaro Narita Aktia, Japan More articles by this author , Takamitsu InoueTakamitsu Inoue Aktia, Japan More articles by this author , Kazuyuki NumakuraKazuyuki Numakura Aktia, Japan More articles by this author , Susumu AkihamaSusumu Akihama Akita, Japan More articles by this author , Mitsuru SaitoMitsuru Saito Akita, Japan More articles by this author , Shigeru SatohShigeru Satoh Akita, Japan More articles by this author , Masatomo MiuraMasatomo Miura Akita, Japan More articles by this author , and Tomonori HabuchiTomonori Habuchi Akita, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.2222AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Even though the dose adjustments during therapy are determined using therapeutic drug monitoring (TDM) in many drugs, only a few molecular targeted agents are monitored by TDM. In this study, we evaluated the pharmacokinetics of sunitinib (SU) in patients who were treated for advanced renal cell carcinoma (aRCC) along with the occurrence of adverse events (AEs) and the treatment outcomes. METHODS The pharmacokinetics of SU was examined in 20 patients with advanced RCC who were treated with the drug. We enrolled 17 males and 3 females in the study. The trough levels of SU and its metabolite N-desethyl sunitinib (DES) were measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS) assays performed on days 1, 3, 5, 7, 14, 21, and 28 in cycle 1 with a pharmacokinetic study performed on day 7. Subsequently, the association of trough levels of SU and DES as measured on day 7 in cycle 1, with patient demographics, existing drug-related polymorphisms, the occurrence of AEs, and treatment outcomes were investigated. RESULTS The area under the concentration–time curve (AUC) for both SU and DES on day 7 revealed significant correlation with the trough levels (R = 0.958 and 0.958, respectively). We observed that the trough levels increased in a dose-dependent manner reaching a plateau on day 10–14. A four-fold difference was observed in the trough levels among patients at the same dose and a negative association was observed between the trough levels and body weight (R = 0.516).However, no association was observed between the trough levels and patients' age (Figure 1). Moreover, no significant differences were observed in the trough levels between the haplotypes of CYP3A5, but there was a tendency toward higher trough levels in patients who had the A allele of ABCG2 421C > A polymorphism (P = 0.085). Furthermore, in cycle 1, trough levels were significantly associated with an occurrence of grade 2 or higher hypothyroidism and fatigue (P = 0.044 and 0.032, respectively; Figure 2) In addition, patients who discontinued sunitinib therapy within 3 weeks had significantly higher trough levels compared with those who continued for 3 weeks or longer (116.8 ± 36.5 vs. 80.4 ± 57.3, P = 0.009; Figure 3). CONCLUSIONS This study suggests the usefulness of TDM during sunitinib therapy in patients with RCC to determine the adequate dose in each patient and thus, prevent severe AEs. However, further studies are necessary to determine the usefulness of TDM in long-term clinical efficacy of sunitinib in aRCC patients. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e755 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Norihiko Tsuchiya Aktia, Japan More articles by this author Nobuhiro Fujiyama Aktia, Japan More articles by this author Shintaro Narita Aktia, Japan More articles by this author Takamitsu Inoue Aktia, Japan More articles by this author Kazuyuki Numakura Aktia, Japan More articles by this author Susumu Akihama Akita, Japan More articles by this author Mitsuru Saito Akita, Japan More articles by this author Shigeru Satoh Akita, Japan More articles by this author Masatomo Miura Akita, Japan More articles by this author Tomonori Habuchi Akita, Japan More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...