Drug Interaction Report

MONITOR: Coadministration with treosulfan may increase the plasma concentrations of drugs that are substrates of CYP450 3A4, 2C19, and/or the efflux transporter P-glycoprotein (P-gp). The proposed mechanism is decreased clearance due to inhibition of these routes of elimination due to treosulfan. According to physiologically-based pharmacokinetic modeling, treosulfan is predicted to be a weak to moderate CYP450 3A4 inhibitor and weak inhibitor of CYP450 2C19, with negligible inhibitory effects on P-gp. However, according to the manufacturer, in vitro studies were unable to exclude potential drug-drug interactions with high plasma concentrations of treosulfan and CYP450 3A4, 2C19, and/or P-gp substrates.

MANAGEMENT: Caution is recommended if treosulfan is coadministered with substrates of CYP450 3A4, 2C19, and/or P-gp, particularly those with a narrow therapeutic range. Some authorities advise that if concomitant use is required, the dosage of these substrates should be administered either 2 hours before or 8 hours after administration of the treosulfan infusion. The prescribing information of the substrates may be consulted for potential dose reductions.

The consumption of grapefruit juice may be associated with increased plasma concentrations of darifenacin. The mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The clinical significance is unknown.