The effects of lapatinib on CYP3A metabolism of midazolam in patients with advanced cancer.

PURPOSE

The potential inhibition of CYP3A4 by lapatinib was studied using midazolam as a probe substrate in patients with cancer.

METHODS

This was a partially randomized, 4-period, 4-sequence, 4-treatment, cross-over study in 24 patients with advanced cancer. Single 1-mg IV and 3-mg oral doses of midazolam were given 2 days apart, in a partially random order, on study days 1, 3, 9, and 11. Lapatinib 1500-mg was administered orally once daily on study days 4 through 11. Midazolam plasma concentrations were measured up to 24-h post dosing, and lapatinib plasma concentrations measured prior to each midazolam dose.

RESULTS

Lapatinib increased the geometric mean (95% CIs) midazolam AUC by 45% (31-60%) after the oral dose and by 14% (0-29%) after the IV dose, and prolonged the midazolam elimination half-life by 48% (22-81%) after the oral dose and by 20% (2-40%) after the IV dose. Lapatinib decreased midazolam total clearance by 13% (1-23%), while total bioavailability was increased 23% (4-46%) without changes in apparent volume of distribution or hepatic bioavailability.

CONCLUSION

These data show that lapatinib caused weak inhibition of gastrointestinal CYP3A4 in vivo. This suggests that oral CYP3A4 drug substrates with a narrow therapeutic index may need dose reduction if lapatinib is to be co-prescribed.