483P - Change in plasma protein binding of SN-38, an active metabolite of irinotecan, in cancer patients with severe renal failure (SRF)

Date 27 September 2014
Event ESMO 2014
Session Poster Display session
Topics Anticancer agents
Cancer in Special Situations
Therapy
Biological Therapy
Presenter Ken-ichi Fujita
Citation Annals of Oncology (2014) 25 (suppl_4): iv146-iv164. 10.1093/annonc/mdu331
Authors K. Fujita1, H. Okumura2, Y. Masuo2, Y. Sunakawa3, K. Shimada4, K. Kawara5, Y. Akiyama5, Y. Sasaki6, Y. Kato2
  • 1Inst Molecular Oncology, Showa University, 1428555 - Tokyo/JP
  • 2Faculty Of Pharmacy, Kanazawa University, Kanazawa/JP
  • 3Internal Medicine, Showa University Northern Yokohama Hospital, Yokohama/JP
  • 4Internal Medicine, Showa University Koto Toyosu Hospital, Tokyo/JP
  • 5Medical Oncology, Saitama Medical University, Hidaka/JP
  • 6Internal Medicine, Showa University, Tokyo/JP

Abstract

Aim

Our previous clinical study revealed that total plasma concentration of SN-38 was higher in cancer patients with SRF than those with normal kidney (NK), although SN-38 is mainly eliminated in the liver. Because SN-38 can bind to plasma protein, we hypothesized the possible increase in unbound fraction of SN-38 and area under the unbound plasma concentration-time curve (AUCu) caused by inhibition of plasma protein binding by uremic toxin(s) in patients with SRF.

Methods

Total and unbound plasma concentrations of SN-38 in the cancer patients treated with 100 mg/m2 irinotecan alone were examined at 1 h after the end of irinotecan infusion to obtain unbound fraction of SN-38. Ex vivo analyses for SN-38 protein binding were performed with plasma samples obtained from 4 respective groups of patients (10-12 for each group) categorized by their renal function, estimated glomerular filtration (eGFR)<15, 15-30, 30-60 and >60 mL/min. The inhibition by 22 uremic toxins known to bind to plasma protein of SN-38 protein binding was also examined.

Results

Unbound fraction of SN-38 in 3 cancer patients with SRF (0.023 ± 0.0060) was significantly higher than that in 5 of those with NK (0.0089 ± 0.0043) (P = 0.0339). AUCu in patients with SRF and those with NK were 0.030 ± 0.015 and 0.0069 ± 0.0043 µM·h, respectively (P = 0.0253). Ex vivo experiments revealed that unbound fractions of SN-38 was inversely correlated with eGFR (Spearman's rank correlation coefficient, -0.5207; P = 0.0003). The unbound fractions in patients with eGFR < 15 mL/min (3.1 ± 0.77) and 15-30 mL/min (2.7 ± 1.0) were significantly higher than those with NK (1.8 ± 1.2) (P = 0.00600 and 0.0409, respectively). An uremic toxin, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF), potently inhibited the plasma protein binding of SN-38 at a clinically relevant concentration to significantly elevate the unbound fraction of SN-38 (0.051 ± 0.013 to 0.10 ± 0.014, P = 0.0000640).

Conclusions

Unbound concentrations of SN-38 were higher in patients with SRF than those with NK. The inhibition of SN-38 protein binding by CMPF is a possible mechanism.

Disclosure

All authors have declared no conflicts of interest.