Drug Interaction Report

CONTRAINDICATED: Coadministration with dolutegravir may increase the plasma concentrations of dofetilide. The proposed mechanism is dolutegravir inhibition of renal organic cation transporter (OCT2) and potentially multidrug and toxin extrusion transporter (MATE) 1. Dolutegravir has been shown in vivo to inhibit tubular secretion of creatinine by inhibiting OCT2. In vitro, dolutegravir inhibits both OCT2 and MATE1. Clinically, high plasma levels of dofetilide may increase the risk of QT interval prolongation, which has been associated with ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Given the risk for serious and/or life-threatening cardiovascular events associated with increased dofetilide plasma levels, concomitant use with dolutegravir is considered contraindicated.

In vitro data suggest that grapefruit juice may inhibit the CYP450 3A4 first-pass metabolism of dofetilide. Decreased first-pass metabolism may increase dofetilide concentrations and increase the risk of QT interval prolongation and arrhythmias. The clinical significance is unknown, since dofetilide has a high oral bioavailability and a low affinity for CYP450 3A4. The manufacturer recommends caution.

Food increases the extent of absorption and slows the rate of absorption of dolutegravir. When administered with a low-, moderate- or high-fat meal, dolutegravir peak plasma concentration (Cmax) increased by 46%, 52% and 67%, systemic exposure (AUC) increased by 33%, 41% and 66%, and time to reach Cmax (Tmax) increased from 2 hours to 3, 4 and 5 hours, respectively, compared to administration under fasted conditions. Dolutegravir may be taken with or without food.