Drug Interactions between emtricitabine / nelfinavir / tenofovir disoproxil and mavorixafor

ADJUST DOSE: Coadministration with potent CYP450 3A4 inhibitors may significantly increase the plasma concentrations and effects of mavorixafor, which is primarily metabolized by the isoenzyme. When a single dose of mavorixafor (200 mg) was coadministered with the strong CYP450 3A4 and P-glycoprotein (P-gp) inhibitor itraconazole (200 mg at steady state), mavorixafor's systemic exposure (AUC) increased approximately 2-fold. The resulting AUC was similar to that expected from a single dose of 400 mg given alone to healthy subjects. Mavorixafor is also a substrate of P-gp, so itraconazole's ability to inhibit this efflux transporter may have contributed to the increase in AUC. Clinical data with potent CYP450 3A4 inhibitors that do not also inhibit P-gp are not available. As mavorixafor causes concentration-dependent QT interval prolongation, an increase in its AUC may increase the risk of experiencing this adverse effect. Likewise, this risk may be further increased if the CYP450 3A4 inhibitor being used also carries a risk of QT prolongation (e.g., adagrasib, ceritinib, clarithromycin, ketoconazole, levoketoconazole, mifepristone, posaconazole, saquinavir, telithromycin, voriconazole).

MANAGEMENT: If mavorixafor must be used concurrently with a potent CYP450 3A4 inhibitor, the daily dose should be reduced to 200 mg. Close monitoring for an increase in adverse effects, such as QT prolongation, is also advised. Any modifiable risk factors for QT prolongation, such as electrolyte abnormalities, should be corrected. The QTc (QT interval corrected for heart rate) should be assessed at baseline and as clinically indicated during concomitant therapy. In addition, the labeling for each medication should be consulted as changes in the QTc interval may require dose adjustments or discontinuation of the drug(s) suspected to be at fault.

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.