Imatinib for hepatocellular cancer--focus on pharmacokinetic/pharmacodynamic modelling and liver function.
The effects of imatinib are partly mediated by the inhibition of platelet-derived growth factor (PDGF), which is highly expressed in the liver. In this phase-I/II trial pharmacokinetic parameters of imatinib given for hepatocellular cancer were similar to those previously derived from CML patients. The AUC of N-desmethyl-imatinib depended on liver function; the metabolism of imatinib was otherwise comparable to other populations. During short-termed imatinib treatment (4 weeks, 400 mg/d), plasma PDGF significantly decreased. The AUC of N-desmethyl-imatinib could best be attributed to the pharmacodynamic effect of PDGF inhibition (r=-0.679 [95% CI: -0.917 to -0.0868], p=0.031).
Treiber
G
G
Department of Gastroenterology/Hepatology/Infectious Diseases, University Hospital, Magdeburg, Germany. ingtre@uks.eu
Wex
T
T
Schleyer
E
E
Troeger
U
U
Hosius
C
C
Malfertheiner
P
P
D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000077214:Becaplermin; D001549:Benzamides; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D015282:Octreotide / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood
D020533:Angiogenesis Inhibitors; D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077214:Becaplermin; D000068877:Imatinib Mesylate; D015282:Octreotide