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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., (© 2020, The American College of Clinical Pharmacology.)

Purpose To validate a plasma vemurafenib steady-state trough concentration (C ss , min ) threshold that predicts survival outcomes of patients with BrafV 600 mutated melanoma., Methods: A pooled analysis of individual patient data from two advanced melanoma trials involving vemurafenib ± cobimetinib therapy was performed. Day 23 was chosen as the landmark time when steady-state concentration reached. Optimal C ss , min threshold was determined via assessment of discriminative performance and model fitting. Association between vemurafenib C ss , min and survival was modelled using Cox proportional hazards regression., Results: Vemurafenib plasma concentration data were available for 402 patients who were on stable dose for the first 3 weeks. When compared to a previously described plasma vemurafenib C ss , min threshold of 42 mg/L, we identified that a cutoff concentration of 50 mg/L by day 23 was strongly associated with progression-free survival and overall survival. The association remained statistically significant after adjusting for important clinical confounding variables. Sub-group analysis showed that while the addition of cobimetinib resulted in a lower day 23 plasma vemurafenib C ss , min , the threshold was still associated with overall survival and not in the monotherapy cohort., Conclusion: A plasma vemurafenib C ss , min threshold of 50 mg/L is strongly associated with survival outcomes in patients with advanced melanoma. This new threshold needs to be validated prospectively in future studies.