K. Fujita,1 Y. Masuo,2 H. Okumura,2 Y. Sasaki,1 Y. Kato2; 1Showa University, Tokyo, Japan, 2Kanazawa University, Kanazawa, Japan
BACKGROUND: Clinical study previously revealed that (a) plasma elimination rate constant of SN-38 was approximately 10-times lower, and (b) unbound SN-38 plasma concentrations were 2-3 times higher in patients with SRF than those with normal kidney (NK), which might cause prolonged neutropenia in patients with SRF. We clarified that (a) was partly caused by the direct inhibition by uremic toxins of OATP1B1-mediated hepatic SN-38 uptake and the down regulation of SLCO1B1 gene expression, and that (b) was induced by the displacement of the SN-38 protein binding by a uremic toxin CMPF. Here, we optimized the irinotecan dose in cancer patients with SRF by establishing PBPK models of irinotecan and SN-38.
METHODS: PBPK models of irinotecan and SN-38 consisting of systemic circulation, liver interstitial fluid and hepatocytes were established with Napp software. Some parameters were cited from literatures. The observed fu of 0.0089 for NK and 0.023 for SRF were used. Other parameters were obtained by fitting of clinical data. Then, we estimated the irinotecan doses in patients with SRF to obtain similar total and unbound PK profiles to those with NK.
RESULTS: PK of irinotecan was well-fitted to the model both in patients with NK and SRF, with almost equal PK parameters. SN-38 PK in patients with NK was also well-fitted to the model. In the fitting of SN-38 PK in patients with SRF, hepatic influx clearance of SN-38 was calculated to be 917 L/h, which was about 3.2-fold lower than that with NK (2890 L/h). The approximately 2/3 and 1/4 irinotecan doses should be appropriate to treat the patients with SRF to obtain similar total and unbound SN-38 PK profiles to those with NK, respectively.
CONCLUSION: Based on atypical properties of SN-38 PK, dose reduction of irinotecan could be considered in treating patients with SRF.