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Effect of Itraconazole, a Potent CYP3A4 Inhibitor, on the Steady‐State Pharmacokinetics of Vemurafenib in Patients With BRAF V600 Mutation–Positive Malignancies
Author(s) -
Zhang Weijiang,
Mathisen Michael,
Goodman Grant R.,
Forbes Harper,
Song Yuyao,
Bertran Enric,
Demidov Lev,
Shin Sang Joon
Publication year - 2021
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.822
Subject(s) - vemurafenib , itraconazole , medicine , pharmacokinetics , dosing , pharmacology , crossover study , confidence interval , area under the curve , adverse effect , urology , gastroenterology , cancer , dermatology , pathology , metastatic melanoma , antifungal , alternative medicine , placebo
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 BRAF V600 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.