A phase I study to determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy male volunteers.

Objectives: To determine the effect of tamoxifen on the pharmacokinetics of a single 250 mg oral dose of gefitinib (IRESSA) in healthy volunteers.

Methods: An open-label, single-center, phase I study in healthy male volunteers. Each volunteer received a single 250 mg oral dose of gefitinib on day 1. On days 11-14, oral loading doses of 60 mg tamoxifen were administered, followed by 20 mg tamoxifen for a further 16 days to maintain steady-state exposure. On day 24, volunteers received a second single 250 mg oral dose of gefitinib. The last dose of tamoxifen was given on day 30. Pharmacokinetic and safety assessments were conducted throughout the trial.

Results: A total of 18 volunteers were recruited. The presence of tamoxifen did not have a clinically significant effect on the primary variables AUC and Cmax of gefitinib, nor on the secondary variables AUC(0-t), tmax, t1/2, and lambdaz. The geometric least square mean values for AUC were 3,407.6 versus 3,397.9 ng.h/ml in the absence and presence of tamoxifen, respectively (90% CL 0.894, 1.112) and for Cmax were 110.8 versus 103.6 ng/ml, respectively (90% CL 0.786, 1.111). The combination of gefitinib with tamoxifen was generally well tolerated by the volunteers. There were no serious adverse events and no volunteer discontinued the study due to an adverse event. NCI-CTC grade 1/2 drug-related adverse events were observed in seven volunteers, including loose stools and skin events associated with gefitinib, and lethargy and headache, flushing, and dizziness associated with tamoxifen.

Conclusions: This study suggests that tamoxifen has no significant effect on the pharmacokinetics, tolerability, or safety of a single 250 mg oral dose of gefitinib. Therefore, in clinical investigations of this combination, no dose adjustment of gefitinib is indicated.