Drug Interactions between fluticasone / vilanterol and mavorixafor

MONITOR: Coadministration with mavorixafor may increase the plasma concentrations of drugs that are substrates of the isoenzyme CYP450 2D6, isoenzyme CYP450 3A4, and/or the efflux transporter P-glycoprotein (P-gp). It is important to determine if the isoenzyme in question is responsible for drug clearance or drug activation as these situations may result in either a potential increase in adverse effects or reduction in efficacy, respectively. When mavorixafor (400 mg) was used concurrently with the sensitive CYP450 2D6 substrate dextromethorphan in healthy subjects, dextromethorphan's peak plasma concentration (Cmax) and systemic exposure (AUC) increased by an average of 6- and 9-fold, respectively. On the other hand, when mavorixafor (400 mg) was used concurrently with the sensitive CYP450 3A4 substrate midazolam in healthy subjects, the Cmax and AUC increased by only 1.1- and 1.7-fold, respectively. Likewise, when a single dose of a transporter cocktail containing P-gp substrate digoxin (0.25 mg) was administered to healthy subjects on mavorixafor (400 mg/day at steady state), digoxin's Cmax and AUC increased by 1.5- and 1.6-fold, respectively. Data for less sensitive substrates or drugs metabolized and/or transported by multiple routes are unavailable.

MANAGEMENT: Caution is advised if mavorixafor is used concurrently with medications that are substrates of the P-gp efflux transporter and/or undergo metabolism via CYP450 2D6 and/or 3A4. This may be particularly important in cases where minimal concentration changes may result in serious adverse reactions from the substrate(s) in question. Dose adjustments and/or increased monitoring may be required. For example, digoxin's serum concentrations should be measured before initiating concomitant use with mavorixafor and as clinically indicated during coadministration. The labeling for the substrate(s) in question should be consulted for more specific recommendations.

MONITOR: Beta-2 adrenergic agonists can cause dose-related prolongation of the QT interval and potassium loss. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). Clinically significant prolongation of QT interval and hypokalemia occur infrequently when beta-2 agonists are inhaled at normally recommended dosages. However, these effects may be more common when the drugs are administered systemically or when recommended dosages are exceeded.

MANAGEMENT: Caution is recommended if beta-2 agonists are used in combination with other drugs that can prolong the QT interval. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

Although they are often combined in clinical practice, the concomitant use of beta-2 adrenergic agonists and corticosteroids may result in additive hypokalemic effects. Since beta-2 agonists can sometimes cause QT interval prolongation, the development of hypokalemia may potentiate the risk of ventricular arrhythmias including torsade de pointes. However, clinical data are limited, and the potential significance is unknown. Patients who are receiving systemic or nebulized formulations of beta-2 agonists, high dosages of inhaled beta-2 agonists, or systemic corticosteroid therapy may be at a greater risk of developing hypokalemia.