The anti-proliferative side effects of AEE788, a tyrosine kinase inhibitor blocking both EGF- and VEGF-receptor, are liver-size-dependent after partial hepatectomy in rats.
BACKGROUND
Blocking of EGFR signaling by the tyrosine kinase inhibitor AEE788 was well tolerated and did not inhibit liver regeneration after standard 70% partial hepatectomy (PH) in a rat model, as demonstrated previously. However, serum levels of AEE788 at POW1 were 3-fold higher than in the non-resected control group. Therefore, we expanded theses studies to a model of extended 90%PH to investigate the role of liver size for the metabolism of AEE788 and its potential influence on side effects, liver regeneration and liver remodeling.


METHODS
Rats treated with 50 mg/kg AEE788 or solvent every other day orally were subjected to 90%PH. Animals were sacrificed at 1, 2, 7 and 28 days after PH. We measured plasma and liver levels of AEE788 and assessed anti-proliferative side effects, liver regeneration, and liver architecture.


RESULTS
Liver regeneration and liver architecture were not impaired by AEE788 treatment after 90%PH. 90%PH caused a clinically relevant drug accumulation within 1 week of treatment (AEE788 serum and tissue levels: 90%PH*>70%PH*>normal control, *p < 0.05), suggesting a liver-size-dependent metabolism of the drug. Drug accumulation after 90%PH was associated with severe side effects (delayed body weight recovery, diarrhea, impaired hair growth) within 1 week of treatment.


CONCLUSIONS
Treatment with AEE788 could be a potential strategy for adjuvant treatment after oncological liver resection, as liver regeneration was not impaired. Our results suggest a liver-size-dependent metabolism of AEE788 leading to drug accumulation and subsequently to severe side effects. It calls for therapeutic drug monitoring in the early postoperative phase after extended resection.
Department of General, Visceral and Transplantation Surgery, University Hospital Essen, Essen, Germany.
Meihong
M
Deng
Hai
H
Huang
Hao
H
Jin
Olaf
O
Dirsch
Uta
U
Dahmen
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006439:Hemodynamics / Q000187:drug effects; D006498:Hepatectomy; D008099:Liver / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D011182:Postoperative Care; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011687:Purines / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016622:Silver Staining; D014841:von Willebrand Factor / Q000378:metabolism
D047428:Protein Kinase Inhibitors; D011687:Purines; D014841:von Willebrand Factor; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788