Nanomedicines in the treatment of emesis during chemotherapy: focus on aprepitant

Abstract

Aprepitant, a selective high-affi nity antagonist of human substance P/neurokinin 1 (NK 1 ) receptors, is the active ingredient of EMEND ® which has recently been approved by the FDA for the prevention of chemotherapy-induced nausea and vomiting (CINV). Aprepitant undergoes extensive metabolism, primarily via CYP3A4 mediated oxidation. It is eliminated primarily by metabolism and is not renally excreted. The apparent terminal half-life in humans ranged from 9 to 13 hours. Early development studies led to the development of a nanoparticle formulation to enhance exposure and minimize food effects. Two large randomized trials accruing 1099 patients studied the effect in patients receiving cisplatin of adding aprepitant to ondansetron and dexamethasone on day 1 then to dexamethasone on days 2 and 3 to control delayed emesis. The complete response of no vomiting and no rescue medication overall from days 1 to 5 improved from 48% to 68% (p<0.001), a 13% improvement in acute emesis but a 21% improvement in delayed emesis with the improvement from 51% to 72% (p<0.001).Similarly, 866 patients treated with cyclophosphamide plus either doxorubicin or epirubicin, received either ondansetron, dexamethasone, and aprepitant on day 1 followed by aprepitant on days 2 and 3 or ondansetron and dexamethasone on day 1 and dexamethasone on days 2 and 3. The overall complete response rate over 5 days was better for the aprepitant group 50.8% vs 42.5% (p=0.015). Complete responses were reported in more patients taking aprepitant in both the acute (76% vs 69%, p=0.034) and delayed (55% vs 49%, p=0.064) phases of vomiting. There were no clinically relevant differences in toxicity by adding aprepitant and improvements in the quality of life of patients on chemotherapy were recorded.

Development of aprepitant, the first neurokinin‐1 receptor antagonist for the prevention of chemotherapy‐induced nausea and vomiting

“…Ultimately, a nanoparticle formulation that enhanced bioavailability and attenuated the food effect was developed using NanoCrystal ® technology, licensed to Merck from Elan/Nanosystems. This process involved media milling of drug particles to <200 nanometers, coating onto beads, and encapsulation to provide a convenient formulation for the patient 17 . EMEND was approved by the U.S. Food and Drug Administration (FDA) in 2003.…”

“…This process involved media milling of drug particles to <200 nanometers, coating onto beads, and encapsulation to provide a convenient formulation for the patient. 17 EMEND was approved by the U.S. Food and Drug Administration (FDA) in 2003. EMEND is dosed orally as a 125 mg tablet on the first day of chemotherapy treatment and as an 80 mg tablet on days two and three after chemotherapy.…”

Discovering and Developing Molecules with Optimal Drug-Like Properties

“…The product, Emend, was launched as a capsule containing sugar beads spray dried with an aprepitant nanosuspension with dosage strengths ranging from 40 to 125 mg. Details of the solid dosage development for Emend are described by Oliver et al (2007).…”

Prevention of chemotherapy-induced nausea and vomiting: focus on fosaprepitant

“…Food effects on the absorption of aprepitant are minimized because of its nanoparticle formulation (Olver et al 2007). …”