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- Title
Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the Steady‐State Pharmacokinetics of Vemurafenib in Patients With BRAF<sup>V600</sup> Mutation–Positive Malignancies.
- Authors
Zhang, Weijiang; Mathisen, Michael; Goodman, Grant R.; Forbes, Harper; Song, Yuyao; Bertran, Enric; Demidov, Lev; Shin, Sang Joon
- Abstract
The effects of itraconazole, a strong CYP3A4 inhibitor, on the steady‐state pharmacokinetics of vemurafenib were evaluated in a phase 1, multicenter, open‐label, fixed‐sequence study. Patients with BRAFV600 mutation–positive metastatic malignancies received oral vemurafenib 960 mg twice daily on days 1 to 20 (period A) and oral vemurafenib 960 mg twice daily with oral itraconazole 200 mg once daily on days 21 to 40 (period B). A mixed‐effects analysis of variance model was used to compare log‐transformed area under the concentration‐time curve during the dosing interval and maximum plasma concentration values for vemurafenib in 8 patients between period B (vemurafenib plus itraconazole) and period A (vemurafenib alone). Multiple doses of itraconazole increased steady‐state exposure of vemurafenib by approximately 40%, with geometric least squares mean ratios (period B/period A) of 140% (90% confidence interval, 121‐161) for both maximum plasma concentration and area under the concentration‐time curve during the dosing interval. There was no apparent increase in incidence or severity of adverse events during coadministration of vemurafenib with itraconazole. In conclusion, coadministration of itraconazole with vemurafenib resulted in a modest increase in exposure of vemurafenib at steady state and was generally well tolerated.
- Subjects
ITRACONAZOLE; PHARMACOKINETICS; ANALYSIS of variance; CONFIDENCE intervals; PROGRESSION-free survival; FAILURE mode &; effects analysis; VEMURAFENIB
- Publication
Clinical Pharmacology in Drug Development, 2021, Vol 10, Issue 1, p39
- ISSN
2160-763X
- Publication type
Article
- DOI
10.1002/cpdd.822