LAUSR

PurposeThe potential inhibition of CYP3A4 by lapatinib was studied using midazolam as a probe substrate in patients with cancer.MethodsThis 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.ResultsLapatinib increased the geometric mean (95% CIs) midazolam AUC(o−∞) 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.ConclusionThese 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.