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- Title
The effects of lapatinib on CYP3A metabolism of midazolam in patients with advanced cancer.
- Authors
Koch, Kevin; Dees, E.; Coker, Shodeinde; Reddy, Nandi; Gainer, Shelby; Arya, Nikita; Beelen, Andrew; Lewis, Lionel; Koch, Kevin M; Dees, E Claire; Coker, Shodeinde A; Reddy, Nandi J; Gainer, Shelby D; Beelen, Andrew P; Lewis, Lionel D
- Abstract
<bold>Purpose: </bold>The potential inhibition of CYP3A4 by lapatinib was studied using midazolam as a probe substrate in patients with cancer.<bold>Methods: </bold>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.<bold>Results: </bold>Lapatinib 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.<bold>Conclusion: </bold>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.
- Subjects
CANCER patients; LAPATINIB; MIDAZOLAM; METABOLISM; DRUG dosage; ANTINEOPLASTIC agents; CROSSOVER trials; HETEROCYCLIC compounds; OXIDOREDUCTASES; TUMORS; THERAPEUTICS
- Publication
Cancer Chemotherapy & Pharmacology, 2017, Vol 80, Issue 6, p1141
- ISSN
0344-5704
- Publication type
journal article
- DOI
10.1007/s00280-017-3470-y