Aprepitant has little inductive effect on CYP3A4 activity when coadministered with dexamethasone

Abstract

Background Aprepitant (APR) is a neurokinin-1 receptor antagonist approved, in combination with a corticosteroid and a 5-hydroxytryptamine3 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting. Corticosteroids and APR both induce CYP3A4 activity and thus this study was conducted to determine if coadministration of APR and a corticosteroid results in significant CYP3A4 induction in vivo. Methods This double-blind, 2-period, crossover study was conducted in 12 healthy subjects to assess the potential inductive effect of a triple-therapy antiemetic regimen versus a dual antiemetic regimen on CYP3A4 activity. Single doses of oral (2 mg) and IV (1 mg) stable isotope (13C515N1) labeled midazolam (MDZ) were simultaneously administered on Days -1 (baseline), 6, 8, 15, and 22 as probes to independently assess the effects on systemic vs systemic+ first pass CYP3A4 activity. (See Table) Results The fold-changes from baseline in oral and intravenous MDZ AUC0-∞ were used as the primary assessments of CYP3A4 activity and are summarized in the table below. The difference between the dual vs triple regimen on days 8, 15, and 22 was primarily due to slight CYP3A4 inhibition by the dual regimen. The mean fold-changes from baseline following the triple antiemetic regimen were all close to 1.0. Conclusion APR, when used in combination with DEX as part of a triple antiemetic regimen, is unlikely to have significant inductive effects on CYP3A4 activity. Clinical Pharmacology & Therapeutics (2005) 77, P73–P73; doi: 10.1016/j.clpt.2004.12.169 Regimen APR Ondansetron (OND) Dexamethasone (DEX) Triple1 D1: 125 mg PO D1: 32 mg IV D1: 12 mg PO D2–3: 80 mg PO D2–4: 8 mg PO Dual D1: 32 mg IV D1: 20 mg PO D2–4: 16 mg PO 1 Doses of DEX were reduced to achieve comparable exposure to dual regimen. MDZ AUC0–∞ Geometric Mean Fold Change† from Baseline†† Ratio of Geometric Mean Fold Change†† (Triple/Double) with 90% CI1 Day TripleRegimen DualRegimen P-value†† Oral MDZ 6 0.84 0.84 1.00 (0.80, 1.25) >0.250 8 0.91 1.45 0.63 (0.49, 0.78) <0.010 15 0.93 1.40 0.66 (0.53, 0.83) <0.010 22 0.83 1.18 0.70 (0.56, 0.88) <0.010 IV MDZ 6 0.90 1.02 0.88 (0.74, 1.03) 0.184 8 0.93 1.25 0.74 (0.63, 0.87) <0.010 15 0.90 1.14 0.79 (0.67, 0.93) 0.017 22 0.94 1.07 0.88 (0.75, 1.04) 0.198 CI= Confidence interval. † Geometric means, CIs, ratios, and fold changes back-transformed from least-squares means from ANOVA, performed on natural log-transformed values †† Tests null hypothesis of no between-treatment difference versus two-sided alternative