Drug Interactions between dabrafenib and Prezcobix

MONITOR: Coadministration with drugs that are inducers of CYP450 3A4 may decrease the plasma concentrations of protease inhibitors (PIs), which are primarily metabolized by the isoenzyme.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, protease inhibitors should be used cautiously with agents that induce CYP450 3A4, particularly if only one PI is used in the antiretroviral regimen. Coadministration of atazanavir without ritonavir and carbamazepine, phenobarbital, or phenytoin is not recommended. Antiretroviral response should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the antiretroviral regimen adjusted as necessary.

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 and/or 2C8 may increase the plasma concentrations of dabrafenib and its active metabolites. In vitro studies have shown that dabrafenib is a substrate of CYP450 3A4 and 2C8, while hydroxy-dabrafenib and desmethyl-dabrafenib are substrates of CYP450 3A4. In a pharmacokinetic study, administration of dabrafenib 75 mg twice daily in combination with the potent CYP450 3A4 inhibitor ketoconazole 400 mg once daily for 4 days increased dabrafenib systemic exposure (AUC) by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. When dabrafenib was given similarly with the potent CYP450 2C8 inhibitor gemfibrozil 600 mg twice daily for 4 days, dabrafenib AUC increased by 47%, but AUC of the metabolites did not change.

MONITOR: Coadministration with dabrafenib may decrease the plasma concentrations of drugs that are substrates of CYP450 3A4, including many of the known inhibitors of the isoenzyme such as conivaptan, delavirdine, nefazodone, telithromycin, and most azole antifungal agents, macrolide antibiotics, and protease inhibitors. Dabrafenib has been found in vitro to be a dose-dependent inducer of CYP450 3A4. Onset of induction is likely to occur after 3 days of repeat dosing with dabrafenib; however, transient inhibition of CYP450 3A4 may be observed during the first few days of treatment. In 12 study subjects, administration of the CYP450 3A4 probe substrate midazolam following repeat doses of dabrafenib 150 mg twice daily for 15 days reduced midazolam peak plasma concentration (Cmax) by 61% and systemic exposure (AUC) by 74%.

MANAGEMENT: The use of dabrafenib with potent CYP450 2C8 inhibitors such as gemfibrozil or potent CYP450 3A4 inhibitors such as ceritinib, clarithromycin, cobicistat, conivaptan, delavirdine, erythromycin, idelalisib, nefazodone, telithromycin, and most protease inhibitors and azole antifungal agents should generally be avoided if possible. Some authorities recommend avoiding concomitant use of dabrafenib during and for 2 weeks after treatment with itraconazole. Otherwise, patients should be closely monitored for development of adverse effects such as febrile reactions (high fever or fever accompanied by rigors, hypotension, dehydration, or renal failure), hyperglycemia, uveitis, and cutaneous malignancies (e.g., squamous cell carcinoma, keratoacanthoma, melanoma). During coadministration of dabrafenib with a CYP450 3A4 inhibitor, the potential for diminished therapeutic effects of the inhibitor should also be considered.