A multicenter phase II trial of the triplet antiemetic therapy with palonosetron, aprepitant, and olanzapine for a cisplatin-containing regimen. - PATROL-I.

Dexamethasone is one of the key antiemetic agents and is widely used even now. However, dexamethasone has been associated with several adverse reactions even after short-term administration. Therefore, developing a steroid-free antiemetic regimen is an important issue to consider. Thus, the purpose of this study was to investigate the efficacy and safety of palonosetron, aprepitant, and olanzapine in a multi-institutional phase II study. Chemotherapy-naive patients scheduled to receive cisplatin were enrolled and evaluated for the occurrence of chemotherapy-induced nausea and vomiting during 120 h after chemotherapy. The primary endpoint of the study was total control (TC) in the overall phase. The key secondary endpoint was complete response (CR), which was assessed in the acute, delayed, and overall phase, respectively. Adverse events were evaluated according to the Common Terminology Criteria for Adverse Events. Eighty-five patients were enrolled from 8 centers in Japan, of which 83 were evaluable for analyses. The percentage of patients who achieved TC during the overall phase was 31.3%. CR was achieved in 61.4%, 84.3%, and 65.1% of patients during the overall, acute, and delayed phases, respectively. The most frequently reported adverse event was anorexia. The primary endpoint was below the threshold and we could not find benefit in the dexamethasone-free regimen, but CR during the overall phase was similar to that of the conventional three-drug regimen. This antiemetic regimen without dexamethasone might be an option for patients for whom corticosteroids should not be an active application.

Effectiveness of Palonosetron, 1-Day Dexamethasone, and Aprepitant in Patients Undergoing Carboplatin-Based Chemotherapy.

INTRODUCTION: Dexamethasone (DEX)-sparing strategy with 5-hydroxytryptamine-3 receptor antagonist (5HT3RA) and aprepitant (APR), as triplet antiemetic prophylaxis, is associated with poor control of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving carboplatin (CBDCA)-based chemotherapy. This study aimed to evaluate whether using palonosetron (PALO) as a 5HT3RA provides superior control with CINV than first-generation (1st) 5HT3RA in triplet antiemetic prophylaxis with a DEX-sparing strategy. METHODS: Pooled patient-level data from a nationwide, multicenter, and prospective observational study were analyzed to compare the incidence of CINV between patients administered PALO and 1st 5HT3RA in combination with 1-day DEX and APR. RESULTS: No significant differences were observed in the incidence of CINV, pattern of CINV, or severity of nausea by type of 5HT3RA in triplet antiemetic prophylaxis with DEX-sparing strategy. In both groups, the incidence of nausea gradually increased from day 3, peaked on day 4 or 5, and then declined slowly. The visual analog scale scores in the delayed phase remained high throughout the 7-day observation period. CONCLUSION: Careful patient selection and symptom monitoring are needed when implementing the DEX-sparing strategy in triplet antiemetic prophylaxis for patients undergoing CBDCA-based chemotherapy. Furthermore, additional strategies may be needed to achieve better control of delayed CINV.

Novel trajectories of the NK1R antagonist aprepitant in rotenone-induced Parkinsonism-like symptoms in rats: Involvement of ERK5/KLF4/p62/Nrf2 signaling axis.

Regulation of the interplay between autophagy and oxidative stress is vital in maintaining neuronal homeostasis during neurotoxicity. The interesting involvement of NK1 receptor (NK1R) in neurodegeneration has highlighted the value of investigating the neuroprotective effect of aprepitant (Aprep), an NK1R antagonist in Parkinson's disease (PD). This study was conducted to disclose Aprep's ability to modulate extracellular signal-regulated kinase 5/Krüppel-like factor 4 (ERK5/KLF4) cue as molecular signaling implicated in regulating autophagy and redox signaling in response to rotenone neurotoxicity. Rotenone (1.5 mg/kg) was administered on alternate days, and rats were given Aprep simultaneously with or without PD98059, an ERK inhibitor, for 21 days. Aprep ameliorated motor deficits as verified by restored histological features, and intact neurons count in SN and striata along with tyrosine hydroxylase immunoreactivity in SN. The molecular signaling of Aprep was illustrated by the expression of KLF4 following the phosphorylation of its upstream target, ERK5. Nuclear factor erythroid 2-related factor 2 (Nrf2) was up-regulated, shifting the oxidant/antioxidant balance towards the antioxidant side, as evidenced by elevated GSH and suppressed MDA levels. In parallel, Aprep noticeably reduced phosphorylated α-synuclein aggregates due to autophagy induction as emphasized by marked LC3II/LC3I elevation and p62 level reduction. These effects were diminished upon PD98059 pre-administration. In conclusion, Aprep showed neuroprotective effects against rotenone-induced PD, which may be partially attributed to the activation of the ERK5/KLF4 signaling pathway. It modulated p62-mediated autophagy and Nrf2 axis which act cooperatively to counter rotenone-associated neurotoxicity pointing to Aprep's prospect as a curious candidate in PD research.

Antiemetic use and chemotherapy induced nausea and vomiting related hospitalization costs after highly or moderately emetogenic chemotherapy.

Aim: Despite numerous available antiemetics, chemotherapy induced nausea and vomiting (CINV) still affects many patients, and CINV related hospitalizations and costs often result. Materials & methods: PrecisionQ analyzed its database to evaluate CINV related hospitalizations and costs following antiemetics use including netupitant/fosnetupitant with palonosetron (NEPA), aprepitant/fosaprepitant with ondansetron (APON) or aprepitant/fosaprepitant with palonosetron (APPA) in patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy. Results: Database analysis identified 15,583 patient records (807 NEPA, 2023 APON, 12,753 APPA) and mean CINV related hospitalization costs were lower across all patients receiving NEPA (US$301) compared with patients receiving APON ($1006, p < 0.0001) or APPA ($321, p < 0.0001). Conclusion: NEPA is associated with lower CINV related hospitalization costs compared with APON and APPA among patients receiving highly emetogenic chemotherapy or moderately emetogenic chemotherapy.

Chemotherapy patients often experience nausea and vomiting that not only has a negative impact on the patient's quality of life but can also result in unplanned hospitalizations with high associated costs. Numerous medications and specific guidelines are available to prevent nausea and vomiting in patients with cancer. Specifically, the combination of two classes of medications (serotonin inhibitors + neurokinin type 1 inhibitors) has been shown to provide the greatest benefit. However, hospitalizations due to nausea and vomiting still occur, and providers require further information to determine the best options for their patients. In this study, the combination of netupitant/fosnetupitant with palonosetron resulted in lower hospitalization costs compared with aprepitant/fosaprepitant with ondansetron or aprepitant/fosaprepitant with palonosetron in chemotherapy patients.

Combination Therapy of Chemotherapy or Radiotherapy and the Neurokinin-1 Receptor Antagonist Aprepitant: A New Antitumor Strategy?

BACKGROUND: Although chemotherapy is predominantly used for cancer treatment, it can be ineffective and can induce serious side effects and lead to chemoresistance. It is essential to discover novel drugs that can enhance the antitumor activity and at the same time, counteract the severe side effects, of chemotherapy. The substance P (SP)/neurokinin-1 receptor (NK-1R) interaction system is known to play a key role in the pathogenesis of cancer. Studies with NK-1R antagonists (such as aprepitant) denote that the NK-1R is a potential target for the treatment of cancer. Aprepitant combined with major chemotherapeutic drugs has shown the potential to increase antitumor activity and decrease side effects. OBJECTIVE: Since malignant tumor cancer cells overexpress the NK-1R, this combination therapy is a promising approach for the treatment of all kinds of cancer. Since aprepitant shows potential of being a broad-antitumor drug, the repurposing of this NK-1R antagonist as an antitumor agent is warranted. Studies pertaining to combination therapy of aprepitant/radiotherapy will also be outlined in this review. The aim of this review is to provide an update on combinational studies pertaining to chemotherapy/radiotherapy and NK-1R antagonist in cancer. CONCLUSION: This combination strategy once confirmed, might open the door to a new era in chemotherapy and radiotherapy with greater antitumor activity and fewer side effects. This treatment strategy could possibly translate into higher cure rates, better quality of life and fewer sequelae in cancer patients.

Aprepitant exerts anti-fibrotic effect via inhibition of TGF-ß/Smad3 pathway in bleomycin-induced pulmonary fibrosis in rats.

Bleomycin is a well-recognized antineoplastic drug. However, pulmonary fibrosis (PF) is considered to be the principal drawback that greatly limits its use. Here, we sought to investigate ability of the neurokinin receptor 1 blocker, aprepitant, to prevent PF caused by bleomycin. Male adult Wistar rat groups were given a single intratracheal injection of bleomycin, either alone or in combination with aprepitant therapy for 3 or 14 days. Collagen deposition and a rise in transforming growth factor beta (TGF-ß) immunoreactivity in lung tissue serve as evidence of bleomycin-induced PF. The serum levels of lactate dehydrogenase, alkaline phosphatase, and total antioxidant improved after aprepitant therapy.Additionally, it reduced the protein expressions of interferon alpha, tumor necrosis factor alpha, and lung lipid peroxidation. Moreover, aprepitant treatment led to an increase in the antioxidant indices glutathione, glutathione peroxidase, and catalase. Aprepitant is postulated to protect against bleomycin-induced PF by decreasing TGF-ß, phosphorylating Smad3, and increasing interleukin 37, an anti-fibrotic cytokine, and G Protein-coupled Receptor Kinase 2. Aprepitant for 14 days considerably exceeded aprepitant for 3 days in terms of improving lung damage and having an anti-fibrotic impact. In conclusion, aprepitant treatment for 14 days may be used as an adjuvant to bleomycin therapy to prevent PF, mostly through inhibiting the TGF-/p-Smad3 fibrotic pathway.

Prolonged administration of aprepitant improves cisplatin-based chemotherapy-induced nausea and vomiting.

Aims: To determine the antiemetic efficacy of a 6-day aprepitant schedule in patients receiving multiple-day cisplatin. Patients & methods: Patients diagnosed with lung cancer and who were chemotherapy-naive were screened. The patients willing to use aprepitant were randomly divided into two groups: prolonged use of aprepitant (PA; 6-day aprepitant) and standard use of aprepitant (SA; 3-day aprepitant); the patients who rejected aprepitant were recruited into the control group (group C). Primary end points included the safety and the number of days without chemotherapy-induced nausea and vomiting. Results: There was no statistical difference in adverse events among the three groups. The average days without chemotherapy-induced nausea and vomiting of group PA (18.28 ± 3.35) was significantly longer than in groups SA and C. Furthermore, better life function scores were achieved in group PA according to the Functional Living Index - Emesis questionnaire. Conclusion: In this study 6-day aprepitant was safe and more effective than standard 3-day aprepitant in controlling chemotherapy-induced nausea and vomiting due to 3-day cisplatin regimens.

The aim of this study was to determine the effectiveness of a 6-day aprepitant schedule in patients receiving a multiple-day highly emetogenic chemotherapy drug (cisplatin). Aprepitant is an important medication used to prevent chemotherapy-induced nausea and vomiting (CINV). The patients willing to use aprepitant were randomly divided into two groups: prolonged use of aprepitant (PA; 6-day aprepitant) and standard use of aprepitant (SA; 3-day aprepitant). The patients who rejected aprepitant were recruited into the control group. The results showed that cases of CINV in group PA ended more quickly. Group PA also had more days with no vomiting and no nausea than the other two groups. The results of this study propose 6-day aprepitant use as more effective to prevent CINV in patients receiving 3-day cisplatin-based chemotherapy.  Clinical trial registration: ChiCTR-IPR-15005933 (http://www.chictr.org.cn).

Antiemetic prophylaxis for chemoradiotherapy-induced nausea and vomiting in locally advanced head and neck squamous cell carcinoma: a prospective phase II trial.

BACKGROUND: There is sparse research reporting effective interventions for preventing nausea and emesis caused by concurrent chemoradiotherapy (CCRT) in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). METHODS: Treatment-naïve LA-HNSCC patients received intensity-modulated radiotherapy with concomitant cisplatin 100 mg/m2 (33 mg/m2/days [d]1-3) every 3 weeks for two cycles. All patients were given oral aprepitant 125 mg once on d1, then 80 mg once on d2-5; ondansetron 8 mg once on d1; and dexamethasone 12 mg once on d1, then 8 mg on d2-5. The primary endpoint was complete response (CR). Pursuant to δ = 0.2 and α = 0.05, the expected CR rate was 80%. RESULTS: A total of 43 patients with LA-HNSCC were enrolled. The median age was 53 years, and 86.0% were male. All patients received radiotherapy and 86.0% of patients completed both cycles as planned. The overall CR rate was 86.0% (95% confidence interval [CI]: 72.1-94.7). The CR rates for cycles 1 and 2 were 88.4% (95% CI: 74.9-96.1) and 89.2% (95% CI: 74.6-97.0). The complete protection rate in the overall phase was 72.1% (95% CI: 56.3-84.7). The emesis-free and nausea-free responses in the overall phase were 88.4% (95% CI: 74.9-96.1) and 60.5% (95% CI: 44.4-75.0), respectively. The adverse events related to antiemetics were constipation (65.1%) and hiccups (16.3%), but both were grade 1-2. There was no grade 4 or 5 treatment-related toxicity with antiemetic usage. CONCLUSION: The addition of aprepitant into ondansetron and dexamethasone provided effective protection from nausea and emesis in patients with LA-HNSCC receiving radiotherapy and concomitant high-dose cisplatin chemotherapy.

Clinical interaction between dexamethasone and aprepitant in chemotherapy for lymphoma.

Aprepitant (Apr) is an effective antiemetic agent for chemotherapy-induced nausea and vomiting (CINV). Current CINV guidelines recommend the antiemetic combination of a 5-HT3 receptor antagonist, Apr, and dexamethasone (Dex) for highly emetogenic chemotherapies. Apr inhibits CYP3A4 dose-dependently. Since Dex is metabolized by CYP3A4, the combined use of Apr and Dex inhibits Dex metabolism. CINV guidelines therefore recommend dose-reduction of Dex when Apr and Dex are used together. However, there is some controversy over whether or not Dex should be reduced when administered as an antitumor agent for lymphoid malignancies. We retrospectively compared the antitumor effect of Dex-containing chemotherapy in which Dex is administered at the usual dose without Apr (group A) or administered at a half-dose in combination with Apr (group B). We analyzed 62 consecutive patients with refractory or relapsed CD20 + B cell lymphoma who received R-DHAP therapy in our hospital, including 29 and 33 cases in groups A and B, respectively. The response rate at the end of the first course of R-DHAP was 62.1% and 54.5%, respectively (P = 0.61). As another endpoint to evaluate the effect of Dex, group B tended to show greater suppression of the lymphocyte count (P = 0.05). Therefore, decreasing the dose of Dex by half appeared to be reasonable when combined with Apr.

NEPA efficacy and tolerability during (neo)adjuvant breast cancer chemotherapy with cyclophosphamide and doxorubicin.

OBJECTIVES: This is a prospective study evaluating NEPA in patients with breast cancer (the NEPA group), who received (neo)adjuvant AC chemotherapy (consisting of doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2). The primary objectives were to assess the efficacy and safety of NEPA in controlling chemotherapy-induced nausea and vomiting (CINV). The secondary objectives were to compare CINV between the NEPA group and historical controls (the APR group) who received aprepitant in an earlier prospective randomised study. PATIENTS AND METHODS: 60 patients participated in the NEPA group; 62 were in the APR group. Eligibility criteria of both groups were similar, that is, Chinese patients with breast cancer who were treated with (neo)adjuvant AC. NEPA group received NEPA and dexamethasone; APR group received aprepitant, ondansetron and dexamethasone. Individuals filled in self-reported diary, visual analogue scale for nausea and Functional Living Index-Emesis questionnaire. RESULTS: Within the NEPA group, 70.0%, 85.7% and 60.0%, respectively reported complete response in the acute, delayed and overall phases in cycle 1 AC. When compared with the historical APR group during cycle 1 AC, NEPA group achieved significantly higher rates of complete response, complete protection, total control, 'no significant nausea' and 'no nausea' in the delayed phase; similar findings were noted in the overall phase with significantly better quality of life. Superior efficacy of NEPA was maintained over multiple cycles. Both antiemetic regimens were well tolerated. CONCLUSION: In this study on Chinese patients with breast cancer who were uniformly receiving AC, NEPA was effective in controlling CINV. TRIAL REGISTRATION NUMBER: NCT03386617.

Improving Guideline-Congruent Care for Chemotherapy-Induced Nausea and Vomiting Prophylaxis in Pediatric Oncology Patients.

PURPOSE: Chemotherapy-induced nausea and vomiting (CINV) is a very common side effect of pediatric cancer therapy. High-quality, evidence-based, pediatric-specific guidelines for prophylaxis and treatment of CINV are available. At many centers, guideline-concordant care is uncommon. We formed a multidisciplinary quality improvement team to implement guideline-concordant care for CINV prophylaxis at our center. We present the results following the first year of our interventions. METHODS: We planned and implemented a multipronged approach in three key phases: (1) developing and publishing an acute CINV prophylaxis pathway, (2) education of providers, and (3) updating the computerized provider order entry system. We used iterative, sequential Plan-Do-Study-Act cycles and behavioral economic strategies to improve adherence to guideline-concordant CINV prophylaxis. We focused on aprepitant usage as a key area for improvement. RESULTS: At the beginning of the study period, < 50% of patients were receiving guideline-concordant CINV prophylaxis and < 15% of eligible patients were receiving aprepitant. After 1 year, more than 60% of patients were receiving guideline-concordant care and 50% of eligible patients were receiving aprepitant. CONCLUSION: We describe the development and implementation of a standardized pathway for prevention of acute CINV in pediatric oncology patients. With a multidisciplinary, multifaceted approach, we demonstrate significant improvements to guideline-congruent CINV prophylaxis.

Use of long term aprepitant as a treatment for refractory nausea following oesophageal stent insertion - a case report.

BACKGROUND: Aprepitant, a substance P neurokinin-1 receptor antagonist, is licenced for the prevention of acute and delayed nausea and vomiting associated with highly and moderately emetogenic cancer chemotherapy. CASE: A 33 year-old male with metastatic gastro-oesophageal cancer had multiple admissions for refractory nausea and vomiting following insertion of an oesophageal stent. ACTION: Mechanical issues with the stent, stent removal and central causes were excluded. Multiple anti-emetic agents were trialled in combination and with varying routes of administration without significant symptomatic improvement. FORMULATION: A trial of aprepitant was proposed as an off-licence therapy. OUTCOME: One hundred sixty-five milligrammes of aprepitant was given orally every 3 days and then up titrated to once daily with significant symptomatic improvement enabling the patient to tolerate an oral diet. The patient remained stable at 12 weeks and has been accepted into two clinical trials for potential further cancer treatment. LESSONS: Aprepitant can be effective in refractory nausea and vomiting outside of emetogenic chemotherapy and safely used as a chronic treatment. The prevalence of refractory nausea and vomiting as a rare adverse outcome post-oesophageal stent insertion should be studied. WHAT NOW?: Further research of neurokinin-1 inhibitors for indications other than chemotherapy-induced nausea and vomiting is indicated.

Effect of aprepitant on kynurenine to tryptophan ratio in cART treated and cART naïve adults living with HIV.

ABSTRACT: Changes in tryptophan metabolism affect human physiology including the immune system, mood, and sleep and are associated with human immunodeficiency virus (HIV) pathogenesis. This study investigates whether the treatment of HIV-infected individuals with the neurokinin-1 receptor antagonist, aprepitant, alters tryptophan metabolism.This study utilized archival samples from 3 phase 1B clinical trials "Anti-HIV Neuroimmunomodulatory Therapy with Neurokinin-1 Antagonist Aprepitant"-2 double-blinded, placebo-controlled, and 1 open-label study. We tested samples from a total of 57 individuals: 26 combination antiretroviral therapy (cART) naïve individuals receiving aprepitant, 19 cART naïve individuals receiving placebo, and 12 individuals on a ritonavir-containing cART regimen receiving aprepitant. We evaluated the effect of aprepitant on tryptophan metabolism by measuring levels of kynurenine and tryptophan in archival plasma samples and calculating the kynurenine to tryptophan ratio.Aprepitant treatment affected tryptophan metabolism in both cART treated and cART naïve individuals with more profound effects in patients receiving cART. While aprepitant treatment affected tryptophan metabolism in all HIV-infected patients, it only significantly decreased kynurenine to tryptophan ratio in cART treated individuals. Aprepitant treatment offers an opportunity to target inflammation and mood disorders frequently co-existing in chronic HIV infection.

Aprepitant in the Treatment of Subacute Sclerosing Panencephalitis: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Aprepitant is a neurokinin-1 receptor antagonist approved for the treatment of chemotherapy-induced nausea. We aimed to investigate the safety and efficacy of aprepitant in patients with subacute sclerosing panencephalitis. METHODS: A randomized, double-blind, placebo-controlled study was conducted in patients with subacute sclerosing panencephalitis assigned to receive two courses of aprepitant 250 mg/day orally or placebo for 15 days with an interval of two months between courses. Primary end points were safety and tolerability, and secondary end point was clinical improvement or stabilization assessed by subacute sclerosing panencephalitis scoring system. Electroencephalography (EEG), brain magnetic resonance imaging, and cerebrospinal fluid measles-specific immunoglobulin G index were evaluated before and after treatment. RESULTS: Sixty-two patients with subacute sclerosing panencephalitis were allocated to aprepitant (n = 31, median age 18 years) or placebo (n = 31, median age 22 years) group. Fifteen patients left the study within the first six months and 12 patients left between six and 12 months. Aprepitant was well tolerated and treatment-associated adverse events were similar to those described in the treatment of nausea. Clinical status at six and 12 months' follow-up did not differ between aprepitant and placebo groups. Post-treatment EEG scores at 12 months were better in the aprepitant group (P = 0.015). Cerebral atrophy on magnetic resonance imaging increased in both groups, whereas measles-specific immunoglobulin G index decreased in the placebo group. CONCLUSIONS: In this first clinical trial of aprepitant treatment in patients with subacute sclerosing panencephalitis, the drug was safe and well tolerated. No clinical effect was observed. A modest improvement in EEG findings might justify trials for longer periods because EEG changes can precede clinical findings in subacute sclerosing panencephalitis.

Safety profile of HTX-019 administered as an intravenous push in cancer patients: a retrospective review.

Objectives: HTX-019 (Cinvanti®) is a novel injectable emulsion formulation of the neurokinin 1 receptor antagonist (RA) aprepitant, approved (as 30-min infusion and 2-min injection) for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). This retrospective analysis evaluated the safety of HTX-019 administered by 2-min injection in patients with cancer.Methods: At a single center, HTX-019 was evaluated as a 2-min injection within a guideline-recommended three-drug regimen for CINV prophylaxis in patients receiving highly (HEC) or moderately emetogenic chemotherapy (MEC). Treatment-emergent adverse events (TEAEs) were assessed 0-60 minutes following initiation of HTX-019 administration, focusing on infusion-site adverse events and hypersensitivity reactions.Results: Among 600 patients (78 MEC, 522 HEC), the most common diagnoses were lung (172) and breast (129) cancer. Patients received a 2-min injection of HTX-019, followed by a 5-hydroxytryptamine type 3 RA intravenously (IV) (palonosetron or ondansetron), dexamethasone IV, and chemotherapy regimen (most common was cisplatin-containing) via a central (76%) and peripheral line (24%). No TEAEs occurred within 60 min after start of HTX-019 administration.Conclusion: HTX-019 administered by 2-min injection has a tolerable safety profile in patients with cancer, representing a viable method of HTX-019 administration for CINV prevention.

Effect of aprepitant administration on CINV caused by cisplatin multi-day chemotherapy and pharmacokinetics of docetaxel.

PURPOSE: To compare efficacy and safety of postponing administration of aprepitant and routine triple-antiemetic treatment for chemotherapy-induced nausea and vomiting in patients who received docetaxel and cisplatin multi-day chemotherapy treatment, and to evaluate the effect of aprepitant on docetaxel pharmacokinetics in the Chinese population. METHODS: A total of 24 cancer patients (including 5 females and 19 males, 22-74 years old) received two cycles of high-emetic DP (docetaxel 75 mg/m2 on day 1 + cisplatin 25 mg/m2 on days 1-3) regimen. A randomized, two-period and cross-over study was applied for prevention of chemotherapy-induced nausea and vomiting. The patients in group A took aprepitant 125 mg on day 1 and 80 mg on days 2-3 (administered aprepitant 1 h before chemotherapy). In group B, the patients took aprepitant 125 mg on day 2, 80 mg on days 3-4, which was delayed 1 day than group A. Efficacy and safety in overall phase were evaluated within 5 days after initiation of chemotherapy. Simultaneously, the differences in the pharmacokinetic parameters of docetaxel between two different antiemetic treatments are compared. RESULTS: The CR rate of delayed-phase nausea was compared between the routine triple-antiemetic treatment (group A) and the aprepitant delayed 1-day administration treatment (group B), and the difference was statistically significant (16.7% vs 45.8% P < 0.05), despite there were similar for two groups in the CR rate of acute-phase nausea and vomiting, and delayed-phase vomiting. In two groups, the area under the docetaxel curve (AUC0-t values) (mean ± SD) of docetaxel was 1134.21 ± 732.55 (ng h/mL) and 1080.94 ± 585.09 (ng h/mL), and the geometric means were 944.82 and 902.10 (ng h/mL), respectively. There was no significant difference in AUC values between the two antiemetic treatments (P > 0.05), as well as Cmax, CLz, T1/2z, MRT and Tmax. CONCLUSIONS: Delayed administration of aprepitant provided superior delayed-phase nausea protection for patients who received cisplatin-based chemotherapy in comparison with the routine triple-antiemetic treatment. In addition, in the routine triple-antiemetic treatment, aprepitant did not significantly affect the main pharmacokinetic parameters of docetaxel.

Aprepitant in Anti-histamine-refractory Chronic Nodular Prurigo: A Multicentre, Randomized, Double-blind, Placebo-controlled, Cross-over, Phase-II trial (APREPRU).

The aim of this multicentre, randomized, double-blind, placebo-controlled, cross-over, phase-II study was to determine the antipruritic effect of aprepitant vs. placebo in 58 patients with anti-histamine-refractory chronic pruritus in chronic nodular prurigo. Patients were randomized to receive either first oral aprepitant 80 mg/day or placebo for 4 weeks. Following a 2-week wash-out phase, the patients were crossed-over to receive the other treatment for 4 weeks. Primary efficacy criterion was the intra-individual difference between mean itch intensity (visual analogue scale) at baseline compared with the end of treatment period. Prurigo lesions, pruritus course, quality of life, patient benefits, and safety were secondary parameters. No significant differences were found between aprepitant treatment and placebo for any of the parameters investigated. Under the experimental conditions of the study, aprepitant, 80 mg daily for 4 weeks, did not have an antipruritic effect in patients with chronic prurigo. (DRKS00005594; EudraCT Number: 2013-001601-85).

Evaluation of aprepitant and fosaprepitant in pediatric patients.

BACKGROUND: Single-dose i.v. fosaprepitant has been approved as an alternative to 3 day oral aprepitant, a neurokinin-1 receptor antagonist, and improves prevention of chemotherapy-induced nausea and vomiting (CINV). Because fosaprepitant has shown similar efficacy to aprepitant in adult patients only, this study compared the efficacy and safety of aprepitant and fosaprepitant in pediatric patients. METHODS: Children younger than 18 years who received aprepitant or fosaprepitant to manage CINV between January 2015 and March 2018 at the National Cancer Center Hospital (Tokyo) were recruited to this study. The primary endpoint was complete response (CR; no vomiting/rescue medication) between 0 and 120 h after the start of chemotherapy. Secondary endpoints were safety based on the frequency of severe adverse events, and evaluation of patient characteristics as risk factors (effect of age and sex). RESULTS: A total of 125 chemotherapy cycles were evaluated. In the aprepitant group, CR was observed in 36 of 80 treatment cycles (45.0%), whereas in the fosaprepitant group, it was observed in 19 of 45 cycles (42.2%; P = 0.852). No treatment-related severe adverse events were observed in either group. The number of non-CR was greater than that of CR in patients aged 6-14 years. The difference in CR rate between male and female patients was not statistically significant (47.1% vs 40.0%, respectively; P = 0.471). CONCLUSIONS: Aprepitant and fosaprepitant were safely used and may be equally useful for pediatric patients receiving highly emetogenic chemotherapy. CR rate may be associated with patient age.

HTX-019 via 2-min injection or 30-min infusion in healthy subjects.

AIM: HTX-019 (CINVANTI® [aprepitant injectable emulsion]) is a neurokinin 1 receptor antagonist approved for preventing acute and delayed chemotherapy-induced nausea and vomiting (CINV). HTX-019 is free of polysorbate 80 and other synthetic surfactants and showed bioequivalence to and a more favorable safety profile than fosaprepitant when administered as a 30-min infusion in healthy subjects. The shortage of small-volume parenteral solutions led to a recommendation to administer HTX-019 by intravenous push. The objectives were to evaluate pharmacokinetics, tolerability and safety following HTX-019 administration by injection versus infusion. MATERIALS & METHODS: Study comprised Part A, a pilot Phase I, single-center, randomized, pharmacokinetic, safety and tolerability, open-label study, followed by Part B, a two-sequence crossover study of HTX-019 130 mg in healthy adults, via injection and infusion. Blood samples were evaluated for aprepitant pharmacokinetics and bioequivalence. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, clinical laboratory testing and electrocardiograms. RESULTS: In Part A, 24 subjects were randomly assigned to three cohorts (n = 8 per cohort) and received HTX-019 130 mg, administered intravenously over 15 min (cohort 1), 5 min (cohort 2) or 2 min (cohort 3). Progression to Part B occurred after acceptable tolerability was established in cohorts 2 and 3. In Part B, 50 randomized subjects received a 2-min injection (9 ml/min) and 30-min infusion (296 ml/h) of HTX-019 130 mg. Bioequivalence was demonstrated for HTX-019 injection and infusion. Both administration methods via a peripheral line were well tolerated; eight subjects experienced 11 TEAEs (six related) following injection and nine experienced 14 TEAEs (nine related) following infusion. Headache and fatigue were the most prevalent treatment-related TEAEs; one subject per group experienced feeling hot ≤30 min after drug administration. CONCLUSION: Pharmacokinetic and tolerability profiles of 2-min HTX-019 injection support this potential alternative administration method for CINV prevention.

Hypersensitivity and infusion-site adverse events with intravenous fosaprepitant after anthracycline-containing chemotherapy: a retrospective study.

AIM: Fosaprepitant, an intravenous neurokinin-1 receptor antagonist for chemotherapy-induced nausea and vomiting, contains polysorbate 80, which is associated with infusion-site adverse events (ISAEs) and hypersensitivity systemic reactions (HSRs). This study investigated ISAEs/HSRs following fosaprepitant with anthracycline-containing chemotherapy. PATIENTS & METHODS: This retrospective chart review noted ISAEs/HSRs following the anthracycline doxorubicin+cyclophosphamide and a three-drug fosaprepitant regimen, via peripheral line. RESULTS: 35/127 patients (28%) developed ISAEs/HSRs with chemotherapy and antiemetic therapy: 32 developed 137 individual ISAEs, primarily erythema, pain and catheter-site swelling; 16 developed 50 individual HSRs, primarily edema/swelling, erythema or dermatitis (no anaphylaxis). CONCLUSION: Fosaprepitant is associated with a significant ISAE/HSR rate following anthracycline-containing chemotherapy via peripheral line. Polysorbate 80-free intravenous neurokinin-1 receptor antagonist may provide a safer chemotherapy-induced nausea and vomiting prophylaxis option.