In vitro,
erlotinib (0-30 µmol/l) and C-labelled
midazolam (MDZ) (5 µmol/l) were incubated with human liver microsomes; separately, microsomes were preincubated with
erlotinib (10 µmol/l) before the addition of MDZ. Results showed a time-dependent inhibition of MDZ metabolism by
erlotinib, with a Ki of 7.5 µmol/l and an inactivation rate constant of 0.009/min. Patients with
cancer (n=24) received a single oral dose of 7.5 mg MDZ and a single intravenous dose of 3 µCi [C-
N-methyl] erythromycin on days 1, 8, 14 and 21. Patients also received 150 mg oral
erlotinib daily from day 8 to day 14. Plasma concentrations of
erlotinib and
OSI-420 were determined on days 8 and 14; MDZ and
1'-hydroxymidazolam were determined on days 1, 8, 14 and 21. Coadministration of
erlotinib resulted in a 4 and a 16% increase in CO2 on days 8 and 14, respectively, after the administration of
erythromycin. The mean AUC0-last of MDZ decreased 17 and 34% after
erlotinib treatment on day 8 and day 14, respectively. The half-life of MDZ and the AUC ratio of
1'-hydroxymidazolam to MDZ were not significantly changed. Although
erlotinib may be a weak mechanism-based irreversible inhibitor of
CYP3A4 in vitro, in vivo,
erlotinib did not inhibit CYP3A-mediated metabolism, as determined by the
erythromycin breath test and the MDZ pharmacokinetics. The mechanism for reduced exposure of MDZ is unclear, but may be because of an increase in intestinal metabolism or decreased absorption. These findings suggest that coadministration of
erlotinib may not result in clinically relevant increases in exposure of
CYP3A substrates.