Drug Interaction Report

MONITOR: Coadministration of berotralstat with drugs that are both substrates of the isoenzyme CYP450 3A4 as well as inhibitors of the efflux transporters P-glycoprotein (P-gp) and/or breast cancer resistance protein (BCRP) may lead to an increase in the plasma concentrations and effects of both drugs. Berotralstat is considered a moderate CYP450 3A4 inhibitor and has been reported in drug interaction studies to increase 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. In addition, berotralstat is a substrate of both P-gp and BCRP. Coadministration with the potent P-gp and BCRP inhibitor cyclosporine increased berotralstat peak plasma concentration (Cmax) and total systemic drug exposure (AUC 0-inf) by 25% and 69%, respectively. Increased plasma concentrations of berotralstat may increase the risk of adverse effects, including the potential for QT prolongation. Berotralstat may cause concentration-dependent prolongation of the Fridericia-corrected QT interval (QTcF). A mean increase in the QTcF interval of 15.9 milliseconds has been reported at three times the recommended dose of berotralstat; however, berotralstat has not been shown to prolong the QT interval to any clinically relevant extent when administered at the recommended daily dose of 150 mg.

MANAGEMENT: During concomitant use of berotralstat with drugs that are substrates of CYP450 3A4, particularly those with a narrow therapeutic index, clinical and laboratory monitoring for patient response and tolerance and individual dose adjustments as needed are recommended. Conversely, while no dose adjustments of berotralstat are recommended, monitoring for adverse events may be advisable during concomitant use of berotralstat with drugs that are also P-gp and/or BCRP inhibitors. Patients should be advised to contact their physician if they experience any undue adverse effects from their medications. Patients should seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope. In addition, the prescribing information for concomitant medications should be consulted and dosages adjusted as needed.

MONITOR: Coadministration with berotralstat may increase the plasma concentrations and effects of drugs that are substrates of the efflux transporter P-glycoprotein (P-gp). The mechanism is decreased clearance due to inhibition of P-gp activity by berotralstat. The administration of a 300 mg dose of berotralstat (twice the recommended daily dose) increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of the sensitive P-gp substrate digoxin, by approximately 1.6-fold and 1.5-fold, respectively. Clinical data are not available.

MANAGEMENT: Caution is advised when berotralstat is coadministered with drugs that are substrates of P-gp, particularly those with a narrow therapeutic index. This interaction has only been reported at twice the recommended daily dose of berotralstat. Clinical and laboratory monitoring should be considered following the initiation or discontinuation of berotralstat, and the individual dosage of the concomitant agents adjusted as needed.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.