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

Autor: Koch KM; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA., Dees EC; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA.; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27514, USA., Coker SA; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA.; Section of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, The Geisel School of Medicine at Dartmouth & The Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA., Reddy NJ; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA.; Section of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, The Geisel School of Medicine at Dartmouth & The Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA.; LGHP Hematology Oncology, 2102 Harrisburg Pike, Lancaster, PA, 17604, USA., Gainer SD; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA., Arya N; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA., Beelen AP; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA.; G1 Therapeutics 4501 Research Commons, Suite 100, Research Triangle Park, NC, 27709, USA., Lewis LD; GlaxoSmithKline, 5 Moore Dr, Research Triangle Park, NC, 27709, USA. Lionel.D.Lewis@Dartmouth.edu.; Section of Clinical Pharmacology and Hematology/Oncology, Department of Medicine, The Geisel School of Medicine at Dartmouth & The Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH, 03756, USA. Lionel.D.Lewis@Dartmouth.edu.
Jazyk: angličtina
Zdroj: Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2017 Dec; Vol. 80 (6), pp. 1141-1146. Date of Electronic Publication: 2017 Nov 02.
DOI: 10.1007/s00280-017-3470-y
Abstrakt: 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 (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.
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.
Databáze: MEDLINE
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