Drug Interactions between benzgalantamine and nirmatrelvir / ritonavir

MONITOR: Coadministration with potent inhibitors of CYP450 2D6 and/or 3A4 may increase the plasma concentrations of galantamine, which is also an active metabolite of benzgalantamine. Up to 75% of galantamine is eliminated via metabolism and in vitro studies have identified CYP450 2D6 and 3A4 as the major isoenzymes involved. The systemic exposure (AUC) of galantamine (4 mg, 8 mg, or 12 mg twice daily) increased by 40%, 45%, and 48%, respectively, when administered to healthy volunteers (n=16) also receiving the strong CYP450 2D6 inhibitor paroxetine. Similarly, the strong CYP450 3A4 inhibitor ketoconazole (200 mg twice daily) increased the AUC of galantamine (4 mg twice daily) by 30% when given concurrently to study subjects (n=16). An increase in the AUC of galantamine can increase the risk of acetylcholinesterase inhibitor-related adverse effects. One potential side effect of galantamine is bradycardia, which may increase the risk of QT prolongation. If the inhibitor being coadministered is also associated with QT prolongation (e.g., adagrasib, ceritinib, fluoxetine, ketoconazole, levoketoconazole, mifepristone), the risk of experiencing this adverse effect may be further increased.

MANAGEMENT: Caution and closer monitoring of the pharmacologic response to galantamine and its prodrug benzgalantamine is advised whenever a potent CYP450 2D6 and/or 3A4 inhibitor is added to or withdrawn from therapy. Some authorities suggest considering a reduction in the galantamine dose for patients on concurrent potent CYP450 2D6 and/or 3A4 inhibitors. Patients should be monitored more closely for acetylcholinesterase inhibitor related adverse effects including vagotonic effects on the heart rate (e.g., bradycardia, which may increase the risk of QT prolongation, and heart block), neurologic side effects (e.g., seizure activity), respiratory distress, bladder outflow obstruction, dizziness or syncope, nausea, vomiting and diarrhea. These effects may be more severe when the coadministered inhibitor shares a similar adverse effect profile with galantamine.