Imatinib for hepatocellular cancer (HCC)—Focus on PK/PD modelling and liver function

Abstract

13088 Background: Imatinib represents standard medical care for treatment of gastrointestinal stroma tumors (GIST) and chronic myeloic leucemia (CML). Indications for other malignancies are evolving, especially in the context of antiangiogenesis, mediated by the inhibition of platelet-derived growth factor (PDGF). Liver metastasis occurs often in GIST patients, usually not affecting liver function. No reliable data about imatinib metabolisation under conditions of true hepatic impairment are available. Methods: Phase-II trial, involving 10 patients with hepatocellular cancer (HCC) as a model disease, we attempted to (1) study short-term changes in serum biomarkers following treatment with octreotide (targeting VEGF) alone or octreotide added by imatinib (400 mg/d, additionally targeting PDGF); (2) to explore a potentially decreased metabolisation of imatinib because of hepatic impairment; and (3) to correlate pharmakokinetic and pharmacodynamic findings (PK/PD modelling). Results: Compared to literature results, PK parameters for imatinib are similiar to patients with normal liver function, however, the main active metabolite N-DMI shows a more prolonged half-life. The AUC of N-DMI depends on liver function as expressed by CPT score (r= −0.67) and serum bilirubine (r= −0.70), p<0.05 each. During short-termed imatinib treatment (4 weeks), plasma PDGF significantly decreased at week 2 compared to controls only receiving octreotide treatment. VEGF secretion was unaffected by imatinib. The AUC of N-DMI could be attributed to the pharmacodynamic effect of PDGF inhibition (r= −0,679 [−0.917 to −0.0868], p = 0.031). Conclusions: In HCC patients with different stages of liver cirrhosis, the metabolisation of N-DMI, but not imatinib, is impaired. PK of imatinib is closely correlated to PDGF inhibition. Whether this translates into antiangiogenesis and tumor regression must be awaited by long term clinical studies. [Table: see text] No significant financial relationships to disclose.