Efficacy, Tolerability and Pharmacokinetic Impact of Aprepitant in Sarcoma Patients Receiving Ifosfamide and Doxorubicin Chemotherapy: A Randomized Controlled Trial

Abstract

Introduction

Aprepitant, a selective neurokinin-1 receptor antagonist approved for prevention of chemotherapy-induced nausea and vomiting (CINV), is an inhibitor of the cytochrome P450 3A4 (CYP3A4) enzyme, which is involved in the clearance of several chemotherapeutic agents. Here we evaluated the efficacy and toxicity of a combination of aprepitant, palonosetron, and dexamethasone as antiemetic prophylaxis in sarcoma patients receiving ifosfamide and doxorubicin chemotherapy, and examined the potential of aprepitant to affect the pharmacokinetics of ifosfamide, which is primarily metabolized by CYP3A4.

Methods

A total of 108 sarcoma patients were randomly assigned to either the aprepitant group (antiemetic regimen: aprepitant, palonosetron, and dexamethasone) or the control group (antiemetic regimen: palonosetron and dexamethasone). Data on nausea, vomiting, and use of rescue medication were collected, and the primary efficacy end point was the proportion of patients with complete response (CR), defined as no vomiting and no use of rescue therapy during 120 h after initiation of chemotherapy. Tolerability was evaluated on the basis of reported adverse events and laboratory assessments. Blood samples for ifosfamide pharmacokinetic analysis were collected in ten patients.

Results

The percentage of patients achieving CR was significantly higher in the aprepitant group compared with that in the control group in the acute, delay, and overall phase (78.4% vs. 59.3%, 74.5% vs. 48.1%, and 68.6% vs. 37.0%, p < 0.05, respectively). No significant differences of adverse events or hematological toxicity were detected between the two groups. Concomitant administration of aprepitant did not cause any statistically significant changes in ifosfamide pharmacokinetics. Values for aprepitant group vs. control group were as follows: geometric mean of C_max was 119 vs. 120 ng/mL, AUC_0–last was 648 vs. 635 ng h/mL, AUC_0–inf was 681 vs. 668 ng h/mL, plasma clearance was 4.40 vs. 4.49 (L/h/m²), respectively; harmonic means of t_1/2 was 2.11 vs. 2.25 h.

Conclusions

This study showed that aprepitant in combination with palonosetron and dexamethasone was safe and effectively controlled CINV in sarcoma patients receiving ifosfamide and doxorubicin chemotherapy. Aprepitant may have a low potential to affect the pharmacokinetics of chemotherapeutic agents metabolized by CYP3A4.

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