Drug Interactions between mavorixafor and terfenadine

MONITOR: Mavorixafor may increase the concentration of CYP450 3A4 and/or P-glycoprotein (P-gp) substrates via inhibition of the isoenzyme and/or the efflux transporter. It is important to determine if CYP450 3A4 is responsible for drug clearance or drug activation as these situations could result in a potential increase in adverse effects or reduction in efficacy, respectively. When mavorixafor (400 mg) was used concurrently with the sensitive CYP450 3A4 substrate midazolam in healthy subjects, midazolam's peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.1- and 1.7-fold (with an upper bound of the 90% confidence interval of 2.1-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 are unavailable.

MONITOR: Mavorixafor can cause dose-related prolongation of the QT interval. Theoretically, coadministration with agents that can also prolong the QT interval may result in additive effects including torsade de pointes, other serious arrhythmias, and sudden death. In a thorough QT study completed in healthy volunteers following the administration of mavorixafor (800 mg), the maximum mean increase in the QTc interval (QT interval corrected for heart rate) was 15.6 ms, with an upper bound of the 90% confidence interval of 19.8 ms. The concentration-QT analysis demonstrated a concentration-dependent increase in the QTc interval. 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 including, but not limited to, congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation may vary depending on the dosage(s) and specific drug(s) involved.

MANAGEMENT: Caution and close clinical monitoring are recommended if mavorixafor is used in combination with a CYP450 3A4 and/or P-glycoprotein (P-gp) substrate that is also capable of QT prolongation, particularly if the QT prolongation is concentration-dependent. If coadministration is necessary, monitoring for an increase in adverse effects (if the medication is cleared by CYP450 3A4 and/or P-gp) or a reduction in efficacy (if the medication is activated by CYP450 3A4) is advised. Due to the risk of QT prolongation from both drugs, modifiable risk factors for QT prolongation (such as electrolyte abnormalities) should be corrected. The QTc interval should be assessed at baseline and during treatment as clinically indicated. A dose reduction, treatment pause, or discontinuation of one or both drugs may be required if changes are observed in the patient's electrocardiogram (ECG). The labeling for both medications should be consulted for more specific recommendations.