Evaluation of Potential Inductive Effects of Aprepitant on Cytochrome P450 3A4 and 2C9 Activity

Abstract

The NK(1) receptor antagonist aprepitant (EMEND(R)), developed for use in combination with a 5HT(3) receptor antagonist and a corticosteroid to prevent highly emetogenic chemotherapy-induced nausea and vomiting (CINV), has been shown to have a moderate inhibitory effect as well as a possible inductive effect on cytochrome P450 (CYP) 3A4. Aprepitant has been noted to produce modest decreases in plasma S(-)-warfarin concentrations, suggesting potential induction of CYP2C9. Because metabolism of some chemotherapeutic agents may involve CYP3A4, the potential inductive effect of the CINV dosing regimen of aprepitant on this metabolic pathway was evaluated using intravenous midazolam, a sensitive probe substrate of CYP3A4. The time course of induction of CYP2C9 by aprepitant was also evaluated using oral tolbutamide, a probe substrate of CYP2C9. In this double-blind, randomized, placebo-controlled, single-center study, 24 healthy subjects were randomized (12 subjects per group) to receive either an aprepitant 3-day regimen (aprepitant 125 mg p.o. on day 1 and aprepitant 80 mg p.o. on days 2 and 3) or matching placebo. All subjects also received probe drugs (midazolam 2 mg i.v. and tolbutamide 500 mg p.o.) once prior to aprepitant dosing (baseline) and again on days 4, 8, and 15. The ratio (aprepitant/placebo) of the geometric mean area under the plasma concentration curve (AUC) fold-change from baseline for midazolam was 1.25 on day 4 (p < 0.01), 0.81 on day 8 (p < 0.01), and 0.96 on day 15 (p = 0.646). The ratio (aprepitant/placebo) of the geometric mean AUC fold-change from baseline for tolbutamide was 0.77 on day 4 (p < 0.01), 0.72 on day 8 (p < 0.001), and 0.85 on day 15 (p = 0.05). Assessed using intravenous midazolam as a probe, aprepitant 125/80 mg p.o. administered over days 1 to 3 produced clinically insignificant weak inhibition (day 4) and induction (day 8) of CYP3A4 activity and no effect on CYP3A4 activity on day 15. Assessed using oral tolbutamide as a probe, the aprepitant regimen also produced modest induction of CYP2C9 activity on days 4 and 8, which resolved nearly to baseline by day 15. Thus, the aprepitant regimen for CINV results in modest, transient induction of CYPs 3A4 and 2C9 in the 2 weeks following administration.

Impact of Age, CYP2C9 Genotype and Concomitant Medication on the Rate of Rise for Prothrombin Time During the First 30 Days of Warfarin Therapy

“…Sulfonylurea use is known to inhibit the metabolism of other drugs in a competitive fashion, 31,32 and sulfonylureas are often used as probe substrates for CYP2C9 activity. 33,34 The potential for a warfarin-sulfonylurea drug interaction is therefore substantial. Data generated in the current study reveal that the association between sulfonylurea use and rate of warfarin anticoagulation is statistically significant (p=0.018).…”

Corticosteroids, the oldest agent in the prevention of chemotherapy-induced nausea and vomiting: What about the guidelines?

“…[21] Aprepitant is a moderate inhibitor and an inducer of cytochrome P450 (CYP) 3A4, as well as an inducer of CYP2C9. [22] For this reason the dosage of dexamethasone has to be decreased by 50% when co-administered with aprepitant. Precautions are recommended with the concomitant use of warfarin, as aprepitant induces its metabolism, causing low international normalized ratio values.…”

Chemotherapy Induced Nausea and Vomiting: Fear Makes the Wolf Bigger than He is

“…Aprepitant is a substrate of, and induces as well as inhibits cytochrome p450 3A4 (CYP3A4). Is also induces CYP2C9 [54]. Hence care must be taken while using other drugs which are known to be metabolised by these enzymes.…”