Drug Interactions between fosaprepitant and glimepiride / pioglitazone

MONITOR: Coadministration with aprepitant or its prodrug, fosaprepitant, may decrease the plasma concentrations of drugs that are primarily metabolized by CYP450 2C9. The mechanism is accelerated clearance due to induction of CYP450 2C9 activity by aprepitant. According to the manufacturer, coadministration of aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 and 3) and the CYP450 2C9 substrate tolbutamide (500 mg orally prior to initiation of aprepitant and on days 4, 8 and 15) resulted in a decrease in tolbutamide systemic exposure (AUC) by 23% on day 4, 28% on day 8, and 15% on day 15. Similarly, healthy subjects stabilized on chronic warfarin therapy given the same regimen of aprepitant had a 34% decrease in S(-) warfarin trough concentration accompanied by a 14% decrease in the INR five days after completion of aprepitant dosing. However, there was no effect on the AUC of R(+) and S(-) warfarin determined on day 3.

MANAGEMENT: Caution is advised if aprepitant or fosaprepitant must be used concomitantly with medications that undergo metabolism by CYP450 2C9, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever aprepitant or fosaprepitant is added to or withdrawn from therapy.

MONITOR: Coadministration with aprepitant or its prodrug, fosaprepitant, may increase the plasma concentrations of drugs that are primarily metabolized by CYP450 3A4. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by aprepitant. According to the manufacturer, administration of the CYP450 3A4 substrate dexamethasone (20 mg orally on day 1 and 8 mg on days 2 through 5) in combination with aprepitant (125 mg single dose on day 1 and 80 mg/day on days 2 through 5) resulted in a 2.2-fold increase in dexamethasone systemic exposure (AUC) on days 1 and 5. Similarly, aprepitant increased the AUC of methylprednisolone (125 mg intravenously on day 1 and 40 mg orally on days 2 and 3) by 1.34-fold on day 1 and 2.5-fold on day 3. The effect of aprepitant on the pharmacokinetics of CYP450 3A4 substrates is expected to be greater when the substrates are administered orally as opposed to intravenously and may be altered following prolonged administration.

MANAGEMENT: Caution is advised when aprepitant or fosaprepitant is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever aprepitant or fosaprepitant is added to or withdrawn from therapy. Chronic, continuous use of aprepitant for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during long-term use.