Drug Interactions between berotralstat and dutasteride / tamsulosin

MONITOR: Coadministration with berotralstat may increase the plasma concentrations and effects of drugs that are substrates of CYP450 3A4 and/or 2D6. The mechanism is decreased clearance due to inhibition of CYP450 3A4 and 2D6 activity by berotralstat. Berotralstat is considered a moderate inhibitor of CYP450 3A4 and 2D6. In drug interaction studies, berotralstat reportedly increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of the sensitive CYP450 3A4 substrate midazolam by approximately 1.5-fold and 2.25-fold, respectively, and the CYP450 3A4 substrate amlodipine by approximately 1.5-fold and 1.75-fold, respectively. It increased the Cmax and AUC of the sensitive CYP450 2D6 substrate dextromethorphan by approximately 2.9-fold and 2.7-fold, respectively, and the CYP450 2D6 substrate desipramine by 1.7-fold and 1.9-fold, respectively. Clinical data are not available.

MANAGEMENT: Caution is advised when berotralstat is coadministered with drugs that are substrates of CYP450 3A4 and/or 2D6, particularly those with a narrow therapeutic index. Clinical and laboratory monitoring are recommended following the initiation of berotralstat, and the individual dosages of the concomitant agents adjusted as needed.

MONITOR: Based on in vitro data, coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of dutasteride, which is metabolized by the isoenzyme. No clinical drug interaction studies have been conducted. However, a population pharmacokinetic analysis found decreased clearance of dutasteride when it is coadministered with the moderate CYP450 3A4 inhibitors, verapamil and diltiazem (37% and 44%, respectively). In contrast, no decrease in dutasteride clearance was seen during coadministration with amlodipine, a calcium channel blocker that is not a CYP450 3A4 inhibitor.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of dutasteride should be considered during concomitant therapy with CYP450 3A4 inhibitors, particularly potent ones like itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics.