Drug interactions between tyrosine kinase inhibitors (gefitinib and erlotinib) and warfarin: Assessment of international normalized ratio elevation characteristics and in vitro CYP2C9 activity.

ABSTRACT

BACKGROUND: Elevation of the international normalized ratio and bleeding complications has been reported in patients taking warfarin concomitantly with tyrosine kinase inhibitors such as gefitinib and erlotinib. OBJECTIVE: To assess the frequency, degree, and onset of international normalized ratio elevation in patients receiving warfarin with gefitinib or erlotinib, and changes in vitro cytochrome P450 2C9 activity. METHODS: This retrospective, single-center, observational study compared international normalized ratio values during the treatment with warfarin in the absence and presence of the tyrosine kinase inhibitors, gefitinib, and erlotinib. In addition, the inhibitory effect of tyrosine kinase inhibitors on cytochrome P450 2C9 activity was screened in an in vitro study. RESULTS: Compared with international normalized ratio at the baseline significant (P < 0.05) international normalized ratio elevations were observed in the majority of the patients (5/6 patients with gefitinib, 83.3%; 6/7 patients with erlotinib, 85.7%) during concurrent therapy. The international normalized ratio was increased 1.8- and 1.6-fold relative to the baseline value, on median, in the presence of gefitinib and erlotinib, respectively, and the onset of international normalized ratio elevation was observed at a median of seven days and nine days, respectively. In vitro (S)-warfarin 7-hydroxylation activity was inhibited by 36% in the presence of 1 µM gefitinib and 27% by 10 µM erlotinib, which are comparable to the steady-state plasma levels of these tyrosine kinase inhibitors after standard dosing. CONCLUSION: In most patients, international normalized ratio elevation was observed within two weeks of the start of concomitant therapy with warfarin and gefitinib or erlotinib. To avoid excessive anticoagulant response by warfarin, international normalized ratio should be carefully monitored weekly and dosage adjustment of warfarin might be recommended during the first month after the start of concurrent tyrosine kinase inhibitor therapy.