229P - Relationship between intestinal function and exposure to sorafenib and sunitinib in cancer patients

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Anti-Cancer Agents & Biologic Therapy
Presenter Jean-Philippe Durand
Authors J. Durand1, B. Blanchet2, M. Buyse3, N. Neveux4, P. Boudou-Rouquette5, O. Mir5, M. Vidal6, L. Cynober7, F. Goldwasser5
  • 1Medical Oncology Unit, Cochin Teaching Hospital, 75014 - PARIS/FR
  • 2Pharmacology-toxicology, Cochin Teaching Hospital, 75014 - PARIS/FR
  • 3Pharmacy, St Antoine Teaching Hospital, PARIS/FR
  • 4Clinical Chemistry Laboratory, Cochin Teaching Hospital, PARIS/GF
  • 5Medical Oncology, Cochin Teaching Hospital, 75014 - PARIS/FR
  • 6Pharmacology-toxicology, Cochin Teaching Hospital, PARIS/FR
  • 7Laboratory Of Biological Nutrition Ea 4466, Université Paris Descartes, PARIS/FR

Abstract

Background

Variability in exposure to sorafenib (SO) and sunitinib (SU), two oral tyrosine kinase inhibitors (TKI) approved for the treatment of various solid tumours, is large. Plasma citrulline (CIT) levels reflect the functional small bowel cell mass. We studied the relationship between TKI exposure and intestinal function in adult cancer patients (pts).

Methods

CIT concentration and drug exposure were determined in 56 pts under SO (n = 38) or SU (n = 18) on day (D) 0 (baseline), then D8 and D22 after treatment initiation. The clinical results led to in vitro studies. In vitro concentration dependent-cytotoxicity of SO and SU was evaluated in Caco-2 cell lines using mitochondrial toxicity test (MTT) assay. Under clinically relevant concentrations of SO (2-10 µg/mL) or SU (0.05-0.10 µg/mL), transepithelial electrical resistance (TEER) and CIT levels at the basolateral side of Caco-2 cells were determined.

Results

In SO-treated pts, mean citrullinemia on D8 was lower than at D0 (26.2 ± 10.9 mmol/L vs 35.2 ± 13.4, p < 0.0001). Baseline citrullinemia correlated with SO Area Under Curve (AUC) (r = 0.59, p =0.0001). Median SO AUC on D22 was 1.23-fold lower than SO AUC on D8 (67.0 vs 82.4 mg/L.h respectively, p = 0.033). Magnitude of decrease in citrullinemia between D0 and D8 correlated with subsequent decrease in SO AUC (r = 0.61, p < 0.001). In SU-treated pts, baseline citrullinemia was not correlated with drug exposure (r = -0.29, p = 0.26). Neither citrullinemia nor SU AUC varied over the study period (p = 0.55 and p = 0.23 respectively). In vitro lethal concentration 50 (LC50) of SO (9.64 + 0.44 µg/mL) was close to therapeutic concentration unlike SU LC 50 (2.07 + 0.11 µg/mL) which was 40-fold higher. In SO-treated Caco-2 cells, TEER and CIT levels decreased compared to those of control group (p < 0.0001 and p = 0.017 respectively). SU did not cause any change of these 2 parameters.

Conclusions

Contrary to SU, SO caused in vitro a cytotoxic effect on Caco-2 cells at therapeutic concentrations. This likely explains the different kinetics of CIT concentrations between SO- and SU-treated pts. Correlation between SO AUC and citrullinemia suggests strongly that functional enterocytic mass contributes to the intra- and inter-individual variability in sorafenib exposure in cancer pts.

Disclosure

O. Mir: BAYER, PFIZER, ROCHE.

F. Goldwasser: BAYER, PFIZER, ROCHE.

All other authors have declared no conflicts of interest.