Drug Interactions between mavorixafor and Phenergan with Dextromethorphan

CONTRAINDICATED: Administration of mavorixafor with substrates of CYP450 2D6 is expected to significantly increase the plasma concentrations and effects of the substrate. The mechanism is decreased clearance due to inhibition of CYP450 2D6 by mavorixafor. Conversely, if the substrate is a prodrug, then mavorixafor would be expected to reduce the plasma concentrations of the active drug and thus its efficacy by inhibiting the prodrug's conversion to an active metabolite(s) via CYP450 2D6. 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 6-fold and 9-fold, respectively. Clinical data are not available with every CYP450 2D6 substrate.

MANAGEMENT: The manufacturer of mavorixafor considers coadministration with drugs that are highly dependent on CYP450 2D6 for clearance to be contraindicated. Likewise, due to the potential for a significant reduction in efficacy, prodrugs which are highly dependent on conversion via CYP450 2D6 for efficacy, like codeine, should also be avoided in combination with mavorixafor.

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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. Following the administration of mavorixafor (800 mg) to healthy volunteers in a thorough QT study, 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% CI of 19.8 ms. The concentration-QT analysis revealed that the increase was concentration-dependent. 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 clinical monitoring are recommended if mavorixafor is used in combination with another medication associated with QT prolongation. Modifiable risk factors for QT prolongation (such as electrolyte abnormalities) should be corrected prior to concomitant use. The QTc should be assessed at baseline and during treatment as clinically indicated. A dose reduction or even discontinuation of one or both drugs may be required. The labeling for both medications should be consulted for more specific recommendations.