Drug Interactions between donepezil and mavorixafor

Consumer information for this interaction is not currently available.

MONITOR CLOSELY: Mavorixafor may increase the concentrations of drugs which are metabolized partly by CYP450 2D6 or primarily via CYP450 2D6 and 3A4 by inhibiting these isoenzymes. 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-fold 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, midazolam's Cmax and AUC increased by an average of 1.1-fold and 1.7-fold (with an upper bound of the 90% confidence interval of 2.1-fold), respectively. Based on these studies, mavorixafor would generally be classified as a strong CYP450 2D6 inhibitor and weak CYP450 3A4 inhibitor. Data for less sensitive or dual CYP450 3A4 and 2D6 substrates are not discussed in the labeling.

MONITOR CLOSELY: 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 2D6 or dual CYP450 3A4 and 2D6 substrate that is also capable of QT prolongation, particularly if the QT prolongation is concentration-dependent given mavorixafor's ability to inhibit these isoenzymes. If coadministration is necessary, monitoring for an increase in adverse effects (if the medication is cleared by these isoenzymes) or a reduction in efficacy (if the medication is activated by these isoenzymes) 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 QT prolongation occurs. The labeling for both medications should be consulted for more specific recommendations.