Aprepitant Research Articles

Aprepitant (AP) versus dexamethasone (D) for preventing delayed emesis induced by anthracyclines plus cyclophosphamide (A+C) chemotherapy (CT) in breast cancer patients (pts): A double-blind, multicenter, randomized study.

9614 Background: A combination of AP + a 5-HT3 receptor antagonist + D and AP alone is recommended, respectively, for the prophylaxis of acute and delayed emesis induced by A+C CT in breast cancer pts. In the registrative study the role of AP in delayed emesis was not defined because prophylaxis of acute emesis was different between the two arms, and the superiority of AP on delayed emesis could be the consequence of a dependent effect on the different results achieved in acute phase. Aim of this study was to compare the efficacy of AP versus D in preventing delayed emesis in pts receiving the same prophylaxis of acute emesis. Methods: A randomized double-blind study comparing AP versus D was completed in naive breast cancer pts treated with A+C. Before CT, all pts were treated with intravenous palonosetron 0.25 mg and D 8 mg, and oral AP 125 mg. On days 2 and 3 pts randomly received D 4 mg bid or AP 80 mg qd. Primary endpoint was rate of complete response (no vomiting, no rescue treatment) from days 2 - 5 after CT. Results: From September 2009 to July 2012, 580 pts were enrolled; 551 were fully evaluated, 273 in arm D and 278 in arm AP. Day 1 complete response rates were similar: 239/273 (87.6%) in D arm and 236/278 (84.9%) in AP arm. From day 2-5, complete response was the same with both antiemetic prophylaxes (79.5%), and all secondary endpoints (complete protection, total control, no vomiting, no nausea, score of FLIE) assumed similar values. During the delayed phase, incidence of insomnia (2.9% vs. 0.4%) and heartburn (8.1% vs. 3.6%) was significantly superior in D arm. Conclusions: In breast cancer pts submitted to A+C CT and receiving the same antiemetic prophylaxis for acute emesis, D and AP present similar efficacy and toxicity. Clinical trial information: NCT 00869973.

Palonosetron (PALO) versus granisetron (GRA) in the triplet regimen with dexamethasone (DEX) and aprepitant (APR) for preventing chemotherapy-induced nausea and vomiting (CINV) in patients (pts) receiving highly emetogenic chemotherapy (HEC) with cisplatin (CDDP): A randomized, double-blind, phase III trial.

9621 Background: Standard antiemetic care for preventing CINV due to HEC is a combination of 5-HT3 receptor antagonist (RA), DEX, and APR. This study compared the efficacy of two 5-HT3drugs, PALO and GRA, in the triplet regimen. Methods: Pts with a malignant solid tumor who were receiving HEC containing 50 mg/m2or more CDDP were enrolled. They were randomly assigned to either Arm A (PALO 0.75 mg, i.v.) or Arm B (GRA 1 mg, i.v.), 30 min before chemotherapy on day 1, both arms with DEX (9.9 mg on day 1 and 6.6 mg on day 2-4, i.v.) and APR (125 mg on day 1 and 80 mg on day 2–3, p.o.). Primary endpoint was complete response (CR; defined as no emetic episodes and no rescue medications) at the overall (0-120 hours) phase. Secondary endpoints included CR at the acute (0-24 h) and delayed (24-120 h) phases, and total control (TC; no emetic episodes, no rescue medications, and no nausea) at the overall, acute, and delayed phases. The planned sample size of 840 provided 90% power to detect a 10% improvement in the CR at 0-120 h with two-sided alpha of 0.05. Primary analysis was conducted with exact Cochran-Mantel-Haenszel (CMH) test. Results: Between July 2011 and June 2012, 842 pts were enrolled and 827 were evaluable. The median CDDP dose was 76.1 mg/m2 in Arm A and 75.7 mg/m2in Arm B. Baseline factors were well-balanced. Efficacy results are summarized in the Table. Conclusions: The present study did not meet its primary endpoint. However, it has shown that the clinical utility of PALO exceeds that of GRA. PALO is a more preferable 5-HT3RA in the triplet regimen than GRA in the prevention of CINV due to HEC. Clinical trial information: 000004863. [Table: see text]

Efficacy of NEPA, a novel combination of netupitant (NETU) and palonosetron (PALO), for prevention of chemotherapy-induced nausea and vomiting (CINV) following highly emetogenic chemotherapy (HEC).

9512 Background: Further progress in preventing CINV will require the introduction of novel agents providing maximal convenience and with efficacy for nausea as well as vomiting. NEPA is a single dose combination of NETU, a novel NK1 receptor antagonist (RA) and PALO, a pharmacologically distinct 5-HT3RA. This study was designed to determine the proper dose of NETU to combine with PALO. Methods: This was a randomized, double-blind, parallel group study in chemotherapy-naïve patients (pts) undergoing cisplatin-based HEC. Four study arms compared 3 oral doses of NEPA (NETU 100, 200, 300mg + PALO 0.50 mg) with oral PALO 0.50 mg, all given on day 1. All pts received oral dexamethasone (DEX) days 1-4. An exploratory aprepitant (APREP) + ondansetron/DEX arm was included. The primary endpoint was complete response (CR: no emesis, no rescue) in the overall (0-120h) phase. Results: 694 pts were enrolled with comparable characteristics across groups: males (57%), median age 55. Common cancers: lung (27%), head and neck (21%). Median cisplatin dose: 75 mg/m2. All NEPA groups showed superior CR rates compared with PALO during the overall and delayed phases, with NEPA300also superior to PALO during the acute phase. NEPA300was also superior to PALO during all phases for no emesis, no significant nausea and complete protection with incremental benefits over lower NEPA doses. AEs were comparable across groups with no dose-response. The % of pts developing ECG changes was comparable across groups. Conclusions: Each NEPA dose resulted in superior CR rates compared with PALO. NEPA300was the best dose studied, with an advantage over lower doses for all efficacy endpoints (including nausea). NEPA doses were well tolerated with similar safety profiles to PALO and APREP. NEPA combined with DEX is superior to PALO plus DEX in prevention of CINV following HEC. [Table: see text]

Determination of Aprepitant in Human Plasma by Using LC-MS/MS with Electrospray Ionization

A precise, sensitive and high throughput liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of Aprepitant (APT) in human plasma was developed and validated using Quetiapine (QTP) as internal standard. The analyte and internal standard were extracted from human plasma using liquid-liquid extraction. Chromatographic separation was performed on Discovery C18 10 cm×4.6 mm, 5 μm column with an isocratic mobile phase composed of 5 mM Ammonium Acetate (pH 4.00):Acetonitrile (10:90), at a flow-rate of 0.9 ml/ min. The MS-MS detection was performed on a AB Sciex API 3200 tandem mass spectrometer operated in Multiple reaction monitoring (MRM) at positive mode at m/z 535.10/277.10 and 384.00/253.10 for APT and QTP respectively. A linear dynamic range of 10.004-5001.952 ng/ml for APT was evaluated with mean correlation coefficient (r) of 0.9991. The precision of the assay (expressed as coefficient of variation, CV) was less than 15% at concentrations of LQC, MQC, HQC and was less than 20% for LLOQQC. Percent recoveries for APT at high, middle and low quality control samples was found to be 71.9%, 68.0%, and 63.8% respectively and for internal standard 77.7%. The analyte was found to be stable throughout five freeze-thawing cycles, bench top, wet extract, dry extract, auto sampler and interim stability studies. Therefore, the proposed method was found to be suitable for the routine quality control analysis of Aprepitant in human plasma in bioequivalence studies.

Inclusion complex of aprepitant with cyclodextrin: evaluation of physico-chemical and pharmacokinetic properties

Objective: Aprepitant (APR) is a water insoluble drug approved for the treatment of chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV). The innovator Emend® is a formulation incorporating drug nanoparticles with good bioavailability (~67%). The objective of the current work was to evaluate the feasibility of formulating a cyclodextrin complex of APR with enhanced solubility/dissolution rate and concomitantly bioavailability.Methods: The complex was prepared using two approaches: kneading and slurry method. The formulated complex was evaluated using DSC, XRPD and FT-IR studies.Results: DSC, XRPD and FT-IR studies confirmed the interaction of β-cyclodextrin with APR indicating formation of a true complex wherein the drug was encapsulated in the cyclodextrin cavity (inclusion phenomenon). In addition to inclusion complexation, non inclusion phenomenon viz., interaction among hydroxyl groups of cyclodextrin and APR was also observed. The saturation solubility and dissolution rate of drug complex was higher than that of aprepitant API. The rate (Cmax) and extent of absorption (AUC) of APR from the complex were found to be comparable to that of Emend® (Reference product).Conclusion: These studies established that cyclodextrin complexation may provide another viable and cost effective option for enhancing solubility and bioavailability of APR.

P1-097 - Correlation between Low-Dose Cyclophosphamide-Induced Hyponatremia and the Use of Aprepitant

ABSTRACT Background For the prevention of nausea/vomiting during anthracyline/cyclophosphamide (CPA) therapy for breast cancer, the use of aprepitant (AP) combined with serotonin antagonist and dexamethasone is recommended. It has been reported that AP does not influence AUC's of 4-hydro-cyclophosphamide, an active metabolite of CPA and DCE, a CPA-metabolite causing nephrotoxicity. Although, in the previous clinical reports for anthracyline/CPA, the toxicities were not significant in patients who were given AP, compared with those without AP, we have experienced several cases of severe hyponatremia probably caused by AP. Occurrence of hyponatremia during chemotherapy might be an issue to be cautious. Methods We investigated serum levels of Na in 67 breast cancer patients who received CPA-combined therapy with the use of AP or not. They all received 600 mg/m2 of CPA combined with either of doxorubicine, epirubicin, or docetaxel. Their prior electrolytes were to be within the normal range. In the first cycle, we evaluated serum Na levels before the CPA start and those of 24 h after. We defined a serum Na level lower than 135 mEq/l as ‘hyponatremia’. Results The background between the two groups, with AP and without AP, was comparable, in whom the prior Na levels were 140.0 ± 1.97 and 140.1 ± 1.88 mEq/l, in the AP group and in the non-AP group, respectively. The chemotherapies including CPA, the clinical stages, the uses of serotonin-receptor antagonist and dexamethasone were comparable between the two groups. Hyponatremia occurred in 11 of 42 (26.2%) patients in the AP group, whereas 2 of 25 patients (8.0%) in the non-AP group. Since the rate in the non-AP group was comparable with the previous reports, hyponetremia seemed to occur frequently in the AP group. The average Na level at 24 h after chemotherapy was 136.429 ± 3.94 mEq/L in the AP group and 138.68 ± 3.05 mEq/l in the non-AP group, respectively. Among 11 patients who developed hyponateremia, they were resolved within 48 h without any treatments in 10 patients and only one needed the Na replacement. The patient did not develop hyponatremia without using AP in the third cycle. Conclusions According to our cohort study, AP might frequently cause hyponatremia in the CPA-combined chemotherapy.

P1-090 - Anti-Emetic Effects in Patients Receiving Carboplatin–Paclitaxel with or without Bevacizumab Categorized as Moderately Emetogenic Chemotherapy in Non-Small-Cell Lung Cancer

ABSTRACT Purpose Palonosetron (PALO), a long-acting second-generation 5-hydroxytryptamine-3 receptor antagonist (5-HT3), and aprepitant (APR), neurokinin-1 receptor antagonist, were previously shown effective to prevent chemotherapy-induced nausea and vomiting (CINV) associated with moderately emetogenic chemotherapy (MEC). This study is to assess the antiemetic effects in the new generation anti-emetics group (NAg): using PALO, granisetron (GRA)–APR and PALO–APR, versus non-NAg: using GRA, on CINV caused by carboplatin (CBDCA)–paclitaxel (PTX) with or without bevacizumab (BV) categorized as MEC for the first time. Methods Clinical characteristics were retrospectively reviewed on 41 in-patients with non-small-cell lung cancer between January 2010 and December 2011. The clinical courses from days 1 to 5 of chemotherapy were observed. Results Anti-emetics administered in this study are NAg (21 cases: 3 are PALO, 4 are GRA–APR and 14 are PALO–APR) and non-NAg (20 cases). Dexamethasone on days 1–3 was in all cases. Complete response (CR: no nausea, no vomiting and no rescue medication) rates were significantly higher (P = 0.020) for NAg than non-NAg (85.7 and 50.0%, respectively). Discussion The results of this study indicate that NAg was significantly superior to CINV on CBDCA–PTX with or without BV.

WS7-1 - Efficacy of Triplet Antiemetic Therapy for Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients Receiving Highly Emetogenic Chemotherapy: Palonosetron, Aprepitant, and Dexamethasone

ABSTRACT Background Chemotherapy-induced nausea and vomiting (CINV) is one of the most problematic symptoms experienced by patients undergoing cancer treatments. Triplet therapy with palonosetron (PALO), aprepitant (APR), and dexamethasone (DEX) is a guideline-recommended antiemetic prophylaxis for highly emetogenic chemotherapy (HEC). However, the efficacy and safety of this therapy for lung cancer patients has not yet been well investigated. Methods Chemotherapy naive lung cancer patients scheduled to receive HEC were enrolled in this study. The eligible patients were pretreated with the triplet therapy (PALO 0.75 mg day 1, APR 125 mg day 1 and 80 mg day 2–3, DEX 9.9 mg day 1 and 8 mg day 2–4) before receiving HEC. The efficacy and safety of these substances were assessed during an observation period starting from the administration of HEC up to 120 h. A questionnaire diary documented patients' complaints. The primary end point was the proportion of the patients who did not experience emesis or rescue antiemetic (Complete Response rate; CR rate) during any part of the whole observation period. The secondary end points were (i) the CR rate during the acute phase (0–24 h) and the late phase (24–120 h), (ii) the proportion of patients who experienced no emetic episodes and significant nausea with no rescue medication (Complete Control rate; CC rate), and (iii) safety. Results A total of 72 patients were enrolled with 54 assessable patients at the time of submission. The median age was 63.5 years. The CR rate during the whole observation period, the acute phase and the late phase was 77.8%, 94.8% and 79.6%, respectively. The CC rate in the late phase was 63.5%. No severe side-effects were observed. Conclusion Triplet therapy using PALO, APR and DEX was shown to be safe and effective in preventing CINV with high CR rates in lung cancer patients treated with HEC. Further investigation is needed to reduce nausea in the late phase.

1578P - Correlation between Cyclophosphamide-Induced Hyponatraemia and the Use of Aprepitant

ABSTRACT Background For prevention of emesis during anthracyline (A)/cyclophosphamide(CPA) therapy for breast cancer, use of aprepitant(AP) combined with serotonin receptor antagonist(5HT3) and dexamethasone(DEX) is recommended. AP, known to function as a CYP3A4 inhibitor, has been reported to interfere with metabolism of chemotherapeutic drugs. It has been also reported that AP does not influence the AUC's of 4-OH and DCE. Although, in the previous clinical reports for AC, the toxicities were not significant in patients who were given AP, compared to those without AP, we have experienced a cases of severe hyponatremia probably related to AP. Thus, we investigated an impact of AP on Na metabolism during chemotherapy using CPA for breast cancer. Material and methods We investigated serum levels of Na in primary breast cancer patients who received CPA-combined therapy with the use of AP as anti-emesis, or not. They all received 600mg/m2 of CPA combined with either of anthracycline or docetaxel. Their ages were to be less than 65 years, and their GFR's were more than 60 ml/min/1.73m2. Their prior electrolytes were to be within normal range. In the first cycle, we evaluated serum Na levels before the CPA start and that at 24 hours after. We defined serum Na level lower than 135 mEq/L as “hyponatremia” based on previous study. We enrolled 81 patients, in whom 52 were given AP and 29 were without AP, between December 2010 and April 2012. Results The background between the two groups, with AP and without AP, were comparable, in whom the median ages were 53.0(33-64) and 53.2(38-65), and the prior Na levels were139.84 ± 1.89 mEq/L, and 140.25 ± 1.82 mEq/L, in the AP-group and in non-AP-group, respectively. The uses of 5HT3 and DEX were similar between the two groups. The incidence of CPA-induced hyponatremia was significantly higher in AP-group than in non-AP-group (26.9% v 6.9%; P =0.04). The average Na level at 24 hours after chemotherapy was 136.32 ± 3.73 mEq/L in AP-group, and 138.60 ± 2.92 mEq/L in non-AP-group. Among 14 patients who developed hyponateremia in AP-group, they were resolved without any intervention in 13, and one needed Na replacement. The patient did not develop hyponatremia without AP in the third cycle. Conclusions According to our cohort study, AP cause hyponatremia more frequently in the CPA-combined chemotherapy. Disclosure All authors have declared no conflicts of interest.

1579P - The Efficacy of Triplet Antiemetic Therapy for Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients Receiving Highly Emetogenic Chemotherapy: Palonosetron (PALO), Aprepitant (APR), and Dexamethasone (DEX)

1579P - The Efficacy of Triplet Antiemetic Therapy for Chemotherapy-Induced Nausea and Vomiting in Lung Cancer Patients Receiving Highly Emetogenic Chemotherapy: Palonosetron (PALO), Aprepitant (APR), and Dexamethasone (DEX)

Difference in the emetic control among highly emetogenic chemotherapy regimens: Implementation for appropriate use of aprepitant

Although antiemetic medication based on the emetogenicity of the cancer chemotherapy regimen is recommended, emetic control varies even among highly emetogenic chemotherapy (HEC). In the present study, we retrospectively investigated the rates of emetic control by a combination of granisetron, 5-HT3 antagonist and dexamethasone in various HEC regimens, including 5 single-day chemotherapy regimens such as gemcitabine/cisplatin (GEM/CDDP), epirubicin/cyclophosphamide (EPI/CPA), pemetrexed or vinorelbine/cisplatin (PEM or VNR/CDDP), doxorubicin/bleomycin/vinblastine/dacarbazine (ABVd) and rituximab/doxorubicin/cyclophosphamide/vincristine/prendisolone (R-CHOP21), and 2 multiple-day chemotherapy regimens such as 5-fluorouracil/cisplatin (5-FU/CDDP) and bleomycin/etoposide/cisplatin (BEP). Complete response (no emesis, no rescue treatment) during the overall period (days 1-5) was assessed as the primary endpoint. Chemotherapy-induced nausea and vomiting was well-controlled (complete response >70%) in GEM/CDDP and R-CHOP21, but not in other regimens. The effect of a triple antiemetic medication including aprepitant (APR) was subsequently examined in patients receiving EPI/CPA and 5-FU/CDDP. Complete response was significantly improved in patients receiving 5-FU/CDDP but not in those receiving EPI/CPA, although the complete protection from vomiting significantly increased in both cases. Of note, the administration of APR for 5 days, but not for 3 days, was required to completely block the incidence of vomiting during the 7 days of the observation period in patients receiving 5-FU/CDDP. These findings suggest that APR should be used appropriately based on the emetogenicity of HEC regimens.

Correlation between low-dose cyclophosphamide-induced hyponatraemia and the use of aprepitant.

e19546 Background: For prevention of nausea/vomiting during anthracyline/cyclophosphamide (CPA) therapy for breast cancer, use of aprepitant (AP) combined with serotonin antagonist and dexamethasone is recommended. It has been reported that AP does not influence AUC’s of 4-hydro-cyclophosphamide, an active metabolite of CPA, and DCE, a CPA-metabolite causing nephrotoxicity. Although, in the previous clinical reports for anthracyline/CPA, the toxicities were not significant in patients who were given AP, compared to those without AP, we have experienced several cases of severe hyponatremia probably caused by AP. Occurrence of hyponatremia during chemotherapy might be an issue to be cautious. Methods: We investigated serum levels of Na in 67 breast cancer patients who received CPA-combined therapy with the use of AP, or not. They all received 600mg/m2 of CPA combined with either of doxorubicine, epirubicin, or docetaxel. Their prior electrolytes were to be within normal range. In the first cycle, we evaluated serum Na levels before the CPA start and those of 24 hours after. We defined a serum Na level lower than 135 mEq/L as “hyponatremia”. Results: The background between the two groups, with AP and without AP, were comparable, in whom the prior Na levels were 140.0 ±1.97 mEq/L, and 140.1 ±1.88 mEq/L, in the AP- and in non-AP-group, respectively. The chemotherapies including CPA, the clinical stages, the uses of serotonin-receptor antagonist and dexamethasone were comparable between the two groups. Hyponatremia occurred in 11 patients out of 42 (26.2%) in AP-group, whereas 2 patients in 25 (8.0%) in non-AP-group. Since the rate in non-AP-group was comparable to the previous reports, hyponetremia seemed to occur frequently in AP-group. The average Na level at 24 hours after chemotherapy was 136.429 ±3.94 mEq/L in AP-group, and 138.68 ±3.05 mEq/L in non-AP-group, respectively. Among 11 patients who developed hyponateremia, they were resolved within 48 hours without any treatments in 10 patients, and only one needed Na replacement. The patient did not develop hyponatremia without using AP in the third cycle. Conclusions: According to our cohort study, AP might frequently cause hyponatremia in the CPA-combined chemotherapy.

Detection of aprepitant drug based on low-dimensional un-doped iron oxide nanoparticles prepared by a solution method

We have prepared as-grown iron oxide nanoparticle by a solution method using reducing agents (urea and NH4OH) in alkaline phase. The nanoparticles were characterized by UV/vis, FT-IR, and Raman spectroscopy, powder X-ray diffraction, and field-emission scanning electron microscopy. They were deposited on a glassy carbon electrode (GCE, surface area, 0.0316cm2) to give a sensor with a fast response towards Aprepitant (APPT) drug in buffer phase. The sensor also exhibits good sensitivity and long-term stability as well as enhanced electrochemical response. The calibration plot is linear (r2=0.9703) over the 2.2nM to 4.1μM APPT concentration range. The sensitivity is ∼2.5316±0.5μAcm−2mM−1, and the detection limit is 0.38±0.02nM (at a signal-to-noise-ratio of 3) in short response time (10s). This method could also be employed for the determination of drugs in quality control of formulation using a reliable I–V method.

Controlling Chemotherapy-Induced Nausea and Vomiting with Neurokinin-1 Receptor Antagonists in Patients on AC-Based Chemotherapy—Are We There Yet?

Chemotherapy-induced nausea and vomiting (CINV) are distressing side effects of chemotherapy. Neurokinin-1 receptor antagonists (NK1-RAs) have been incorporated in the contemporary management of CINV. However, clinical studies on NK1-RAs have shown mixed results in reducing CINV risk. Most studies focused on the use of aprepitant (APR) and casopitant (CAS) in breast cancer patients receiving AC-type (doxorubicin and cyclophosphamide) chemotherapy. In this study, we compared the study design and clinical efficacies of these NK1-RAs in reducing CINV risk. Among the selected eight studies, 4 APR Randomized Controlled Trials (RCTs), 2 APR Observational Studies (OSs) and 2 CAS RCTs were identified. Patient-related characteristics such as the proportion of females (60.0% - 100.0%), age (46.5 - 59.5 years), histories of motion (5.6% - 47.0% in NK1-RA arms) and morning sicknesses (14.2% - 45.0% in NK1-RA arms) and types of antiemetic regimens; as well as chemotherapy-related characteristics such as the proportion of patients on AC chemotherapy (15.0% - 100.0%) varied greatly. In terms of efficacies, both APR and CAS improved overall CR and vomiting in majority of the studies. None of the studies, however, demonstrated that NK1-RA could provide adequate nausea control. To conclude, NK1-RAs are effective in improving vomiting and overall CR, but not useful in controlling nausea or attaining CC, the ideal CINV endpoint. A shift in paradigm is needed for future CINV research. As healthcare providers continue to strive for optimum CINV control in their patients, we hope this review can help them make better informed clinical decisions.

Development and Validation of a New RP-HPLC Method for the Determination of Aprepitant in Solid Dosage Forms

Purpose: To develop and validate a new, simple, sensitive, rapid, cost-effective and accurate reverse phase-high performance liquid chromatography (RP-HPLC) method for the determination of aprepitant (APT) in capsule dosage form.Methods: The method developed for the determination of APT in capsule formulation involved using RP-HPLC which incorporated a C18 column 250 x 2.5 mm i.d, 5 μm particle size, in isocratic mode, with mobile phase comprising of methanol: water in the ratio of 90:10 (v/v). The flow rate was 1 mL/min and the detection was monitored at 220 nm. The total run time was 10 min and the column was maintained at ambient temperature.Results: APT was eluted in the given mobile phase with a retention time (tr) of 4.473 min. The linearity for the quantification of APT was 0.1 - 10 μg/mL (R2 =0.989, Y= 33032x + 71501) with coefficients of variation (based on mean peak area for six replicate injections) in the range 0.04 to 0.132. The limits of detection and of quantification were 0.028 and 0.094 μg/mL, respectively. Recovery of the method was 99.56 - 100.5 % while the relative standard deviation (RSD) of intra-day and inter-day precision was 0.85 and 1.05, respectively. System precision and method precision were 0.013 and 1.400 %, respectively. The specificity data of the proposed method indicated that excipients in the capsules did not interfere with the drug peak. Furthermore, the well-shaped peaks buttressed the specificity of the method.Conclusion: The proposed RP-HPLC method is simple, sensitive, rapid, cost-effective and accurate for the determination of APT in both bulk materials and pharmaceutical dosage forms.Keywords: Aprepitant, RP-HPLC, Isocratic, Pharmaceutical dosage forms, Analysis, Validation

Olanzapine Versus Aprepitant for the Prevention of Chemotherapy-Induced Nausea and Vomiting: A Randomized Phase III Trial

The purpose of the study was to compare the effectiveness of olanzapine (OLN) and aprepitant (APR) for the prevention of chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly emetogenic chemotherapy. A phase III trial was performed in chemotherapy-naive patients receiving cisplatin ≥ 70 mg/m(2) or cyclophosphamide ≥ 500 mg/m(2) and doxorubicin ≥ 50 mg/m(2), comparing OLN to APR in combination with palonosetron (PAL) and dexamethasone (DEX). The OLN, PAL, DEX (OPD) regimen was 10 mg of oral OLN, 0.25 mg of IV PAL, and 20 mg of IV DEX prechemotherapy, day 1, and 10 mg/day of oral OLN alone on days 2-4 postchemotherapy. The APR, PAL, DEX (APD) regimen was 125 mg of oral APR, 0.25 mg of IV PAL, and 12 mg of IV DEX, day 1, and 80 mg of oral APR, days 2 and 3, and 4 mg of DEX BID, days 2-4. Two hundred fifty-one patients consented to the protocol and were randomized. Two hundred forty-one patients were evaluable. Complete response (CR) (no emesis, no rescue) was 97% for the acute period (24 hours postchemotherapy), 77% for the delayed period (days 2-5 postchemotherapy), and 77% for the overall period (0-120 hours) for 121 patients receiving the OPD regimen. CR was 87% for the acute period, 73% for the delayed period, and 73% for the overall period in 120 patients receiving the APD regimen. Patients without nausea (0, scale 0-10, MD Anderson Symptom Inventory) were OPD: 87% acute, 69% delayed, and 69% overall; APD: 87% acute, 38% delayed, and 38% overall. There were no grade 3 or 4 toxicities. CR and control of nausea in subsequent chemotherapy cycles were equal to or greater than cycle 1 for both regimens. OPD was comparable to APD in the control of CINV. Nausea was better controlled with OPD. In this study, OLN combined with a single dose of DEX and a single dose of PAL was very effective at controlling acute and delayed CINV in patients receiving highly emetogenic chemotherapy. CR rates were not significantly different from a similar group of patients receiving highly emetogenic chemotherapy and an antiemetic regimen consisting of APR, PAL, and DEX.

Imaging Drugs with and without Clinical Analgesic Efficacy

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

The effect of a 3-day oral aprepitant regimen on the prevention of CINV over standard therapy in Chinese patients receiving high-dose cisplatin.

9105 Background: Clinical studies have shown that Aprepitant (APR), a Neurokinin-1 receptor antagonist, is efficacious in preventing chemotherapy induced nausea and vomiting (CINV) and well tolerated. The efficacy, safety, and tolerability of APR in Chinese patients have not been studied. In this phase III, multicenter, double-blind, placebo-controlled, randomized study, we assessed the efficacy, safety, and tolerability of a 3-day oral APR regimen compared with that provided by a standard therapy regimen (ST) in Chinese patients. Methods: Four hundred twenty-one patients receiving chemotherapy including cisplatin (≥70 mg/m2) were randomly assigned (1:1) to receive the APR regimen (APR 125 mg po d1 and 80 mg d2-3, granisetron 3 mg iv d1, DEX 6 mg po d1, and 3.75 mg d2-4) (n=209) or the ST (placebo d1-3, granisetron 3 mg iv d1, and DEX 10.5 mg d1 and 7.5 mg d2-4) (n=212). The primary endpoint was the percentage of patients with complete response (CR; no emesis and no use of rescue therapy) in the overall phase (0 – 120 hours after chemotherapy); secondary endpoints were no vomiting (NV), time to first vomiting episode, and patient-reported impact of CINV on daily life. Results: Overall baseline characteristics were balanced between two arms. All patients received at least one dose of treatment drug and had at least one post-treatment assessment. The proportions of patients with CR in the overall phase were 69.6% in the APR regimen and 57.0% in the ST regimen (p=0.007). The proportions of patients with NV were 70.6% and 57.0%, respectively (p=0.003). Results from the Quality of Life questionnaire showed significant differences between the APR and ST in two of the vomiting domains: ‘ability to enjoy a meal’ (76.0% vs. 66.3%; p<0.05) and ‘hardship on others’ (78.0% vs. 67.3%; p<0.05). The incidence of adverse events was generally similar in both treatment groups. In addition, the distribution of toxicity grades was also generally similar between groups. Conclusions: In our study, the addition of APR to the standard antiemetic treatment regimen was superior in preventing CINV and was well tolerated compared with the ST alone in Chinese patients undergoing cisplatin therapy.

Aprepitant for Erlotinib-Induced Pruritus

Aprepitant for Erlotinib-Induced Pruritus

A comparison of the combination of aprepitant and dexamethasone versus the combination of ondansetron and dexamethasone for the prevention of postoperative nausea and vomiting in patients undergoing craniotomy

A comparison of the combination of aprepitant and dexamethasone versus the combination of ondansetron and dexamethasone for the prevention of postoperative nausea and vomiting in patients undergoing craniotomy