Hyeong-Seok Lim* (1), Young-Woo Kim (2), Keun Won Ryu (2), Jun Ho Lee (2), Young-Iee Park (2), Sook Ryun Park (2)
1) Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, Ulsan University College of Medicine, Pungnap-2-dong, Seoul, Republic of Korea (2) Research Institute and Hospital, National Cancer Center, 809 Madu 1, Ilsan, Goyang, Gyeonggi, 410-769, Republic of Korea
Objectives: S-1 is an oral 5-Fluorouracil (5-FU) agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. Tegafur is converted into 5-FU in body, which is an effector. CDHP induces long-term retention of an increased concentration of 5-FU in blood by reversibly inhibiting dihydropyrimidine dehydrogenase [1]. This study explored the pharmacokinetics (PK) of S-1, and PK changes after gastric surgery in patients with gastric cancer.
Methods: Serial blood samples were collected on day 1 of cycle 1 for the PK from 37 patients. Patients were 18-70 years old, biopsy-proven locally advanced gastric cancer of clinical stage of IIIA, IIIB, or IV (M0) [2]. Blood was drawn before (0 h) and at 0.5, 1, 1.5, 2, 4, 6, 8, and 12 h after treatment initiation on day 1 and pre-dose on day 8 of each 1st cycle of preoperative and postoperative treatment. Plasma concentrations of tegafur, 5-FU, CDHP were measured using liquid chromatography-tandem mass spectrometry. PK was analyzed by non-compartmental (NCA) methods using WinNonlin® 5.2 (Pharsight Corporation, Mountain View, CA), and by compartmental modeling using NONMEM® 7.2 (ICON Development Solutions, USA). In modeling analysis, PK models for tegafur and 5-FU were fitted sequential, with individual parameter estimates of tegafur as input for 5-FU model. CHDP concentration data were modeled separately, and the predicted CHDP concentrations were incorporated in the tegafur and 5-FU model as a time varying covariate which inhibits the clearance of 5-FU by inhibitory Emax model.
Results: In the NCA analysis, the PK’s of tegafur and 5-FU before and after gastric surgery were similar except for higher maximum average concentrations of 5-FU. Medan Tmax of tegafur was shorter after surgery with no statistical significance. In the modeling analysis, tegafur were best fitted by mixed zero and first order absorption model and two compartment disposition model. 5-FU was best described by one compartment disposition model. The tegafur model was significantly improved when the different first order (Ka), zero order absorption (D1), and absorption lag (ALAG1) parameters were included before and after gastric surgery. However, in Monte-Carlo simulation, plasma concentration profiles of tegafur and 5-FU were very similar between before and after the surgery. There was a significant improvement in the tegafur and 5-FU model when the model-predicted CDHP concentrations were incorporated.
Conclusions: Although there were statistically significant findings on the changes of absorption processes after gastric surgery, the changes were so small that the clinical significances should be evaluated by further studies. This study also evaluated the PK with the quantification of the effect of CDHP on the 5-FU PK.
References:
[1] Saif MW, Rosen LS, Saito K, Zergebel C, Ravage-Mass L, Mendelson DS. A phase I study evaluating the effect of CDHP as a component of S-1 on the pharmacokinetics of 5-fluorouracil. Anticancer Res. 2011 Feb;31(2):625-32.
[2] Japanese Gastric Cancer A. Japanese Classification of Gastric Carcinoma – 2nd English Edition. Gastric Cancer 1998; 1: 10-24.
Reference: PAGE 22 (2013) Abstr 2718 [www.page-meeting.org/?abstract=2718]
Poster: Oncology