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Drugs that Inhibit or Induce Drug-Metabolizing Enzymes: Dabrafenib is primarily 158 metabolized by CYP2C8 and CYP3A4. Strong inhibitors or inducers of CYP3A4 or CYP2C8 may increase or decrease, respectively, concentrations of dabrafenib. Substitution of strong inhibitors or strong inducers of CYP3A4 or CYP2C8 is recommended during treatment with Dabrafenib. If concomitant use of strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) or strong inducers (e.g., rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8 is unavoidable, monitor patients closely for adverse reactions when taking strong inhibitors or loss of efficacy when taking strong inducers.
Drugs that alter the pH of the upper GI tract (e.g., proton pump inhibitors, H2-receptor antagonists, antacids) may alter the solubility of dabrafenib and reduce its bioavailability. However, no formal clinical trial has been conducted to evaluate the effect of gastric pH-altering agents on the systemic exposure of dabrafenib. When Dabrafenib is coadministered with a proton pump inhibitor, H2-receptor antagonist, or antacid, systemic exposure of dabrafenib may be decreased and the effect on efficacy of Dabrafenib is unknown.
Dabrafenib induces CYP3A4 and may induce other enyzmes including CYP2B6, CYP2C8, CYP2C9, CYP2C19, and UDP glucuronosyltransferases (UGT) and may induce transporters. Dabrafenib decreased the maximum concentration (Cmax) and area under the curve (AUC) of midazolam (a substrate of CYP3A4) by 61% and 74%, respectively. Coadministration of Dabrafenib with other substrates of these enzymes, including warfarin, dexamethasone, or hormonal contraceptives, can result in decreased concentrations and loss of efficacy. Substitute for these medications or monitor patients for loss of efficacy if use of these medications is unavoidable.
from FDA,2013.05
