Elinzanetant, a new combined neurokinin-1/-3 receptor antagonist for the treatment of postmenopausal vasomotor symptoms.

INTRODUCTION: In many postmenopausal women, quality of life is decreased due to vasomotor symptoms. Efficient and well-tolerated non-hormonal treatment options are needed. AREAS COVERED: The present review summarizes what is known about the etiology of postmenopausal vasomotor symptoms as a rationale for the mechanism of action of Elinzanetant, a new neurokinin (NK)-1/-3 receptor antagonist, as well as its efficacy and side effect profile. EXPERT OPINION: Elinzanetant likely exerts an antagonistic effect on the NK-3 receptor in the preoptic thermoregulatory zone, but also an additional antagonistic effect on the NK-1 receptor possibly leading to a reduction in vasodilatation and heat-sensing neuro-activity. Elinzanetant's reported peak drug concentrations are reached within one hour and the terminal elimination half-life is approximately 15 hours. Two phase IIb clinical trials evaluated the safety profile and efficacy of several doses. There were no serious adverse events, which also included a lack of evidence of drug-related hepatotoxicity. Overall, Elinzanetant seems to be well-tolerated. In the SWITCH-1 study, the 120 mg/day and 160 mg/day regimen showed good efficacy for the treatment of vasomotor symptoms and led to significant improvements in quality of life. Thus, 120 mg oral Elinzanetant/day was used in phase III trials, whose results have not yet been published.

A pharmacological overview of aprepitant for the prevention of postoperative nausea and vomiting.

INTRODUCTION: Post-operative nausea and vomiting (PONV) affects 30% of all patients undergoing surgery and up to 80% of high-risk patients. Antiemetics for PONV prophylaxis target a variety of receptor systems, with varying degrees of efficacy and side effect profile. Neurokinin -1 receptor antagonists are the most recent class of compounds investigated for PONV prophylaxis, with aprepitant being the only one currently approved for this indication. AREAS COVERED: This review covers the pathophysiology of PONV, current recommendations for PONV prophylaxis, pharmacokinetics, and pharmacodynamics of aprepitant, and the evidence for its efficacy in the management of PONV as a single agent and in combination therapy. EXPERT OPINION: Aprepitant is effective for PONV prophylaxis. It has superior antivomiting efficacy, long half-life, and favorable side effect profile. Data on antiemetic combinations involving aprepitant are limited, and it is not clear if the addition of other antiemetics to aprepitant results in improved PONV prophylaxis. The oral route of administration of aprepitant is a potential limitation in a busy clinical practice. However, the recent approval of an intravenous formulation could provide a more convenient route of administration. Aprepitant remains more expensive than other antiemetics, and there are no studies assessing the cost effectiveness of its use.

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.

Challenges in the Development of Intravenous Neurokinin-1 Receptor Antagonists: Results of a Safety and Pharmacokinetics Dose-Finding, Phase 1 Study of Intravenous Fosnetupitant.

Oral NEPA is the fixed-combination antiemetic comprising netupitant (neurokinin-1 receptor antagonist [NK1 RA]) and palonosetron (5-hydroxytryptamine-3 receptor antagonist [5-HT3 RA]). Intravenous (IV) NEPA, containing fosnetupitant, a water-soluble N-phosphoryloxymethyl prodrug of netupitant, has been developed. Fosnetupitant does not require excipients or solubility enhancers often used to increase IV NK1 RA water solubility, preventing the occurrence of hypersensitivity and infusion-site reactions associated with these products. In this phase 1 study, subjects received a 30-minute placebo or fosnetupitant (17.6-353 mg) infusion and an oral NEPA or placebo capsule, with 2-sequence crossover treatment for fosnetupitant 118- to 353-mg dose cohorts. IV fosnetupitant safety and pharmacokinetics were evaluated, and its equivalence to an oral netupitant 300-mg dose was defined. Overall, 158 healthy volunteers were enrolled. All adverse events (AEs) were mild or moderate in intensity. Doppler-identified infusion-site asymptomatic thrombosis occurred in 5.4% (fosnetupitant) and 1.2% (oral NEPA) of subjects. The frequency or number of treatment-related AEs did not increase with ascending fosnetupitant doses. The most common treatment-related AEs were headache (fosnetupitant, 8.1%; oral NEPA, 12.7%) and constipation (fosnetupitant, 1.4%; oral NEPA, 7.5%). A fosnetupitant 235-mg dose was equivalent, in terms of netupitant exposure, to 300-mg oral netupitant. The safety profile of a single fosnetupitant 235-mg infusion was similar to that of single-dose oral NEPA.

Randomized, Double-Blind, Phase III Study of Fosnetupitant Versus Fosaprepitant for Prevention of Highly Emetogenic Chemotherapy-Induced Nausea and Vomiting: CONSOLE.

PURPOSE: We evaluated the efficacy and safety of fosnetupitant (FosNTP) versus fosaprepitant (FosAPR) for preventing highly emetogenic chemotherapy-induced nausea and vomiting. This phase III study was the first head-to-head comparison between two different neurokinin-1 receptor antagonists in combination with palonosetron and dexamethasone. PATIENTS AND METHODS: Patients scheduled to receive cisplatin-based chemotherapy were randomly assigned 1:1 to FosNTP 235 mg or FosAPR 150 mg in combination with palonosetron 0.75 mg and dexamethasone. The primary end point was overall (0-120 hours) complete response (CR; no emetic event and no rescue medication) rate, stratified by sex and age category, to show the noninferiority of FosNTP to FosAPR (noninferiority margin, -10% for the difference in the overall CR rate). RESULTS: Overall, 795 patients were randomly assigned, of whom 785 received the study drug (FosNTP [N = 392] v FosAPR [N = 393]) and were evaluated for efficacy and safety. The overall CR rate was 75.2% versus 71.0%, respectively (Mantel-Haenszel common risk difference, 4.1%; 95% CI, -2.1% to 10.3%), demonstrating noninferiority of FosNTP to FosAPR. The CR rates in the acute (0-24 hours), delayed (24-120 hours), and beyond delayed (120-168 hours) phases, and at 0-168 hours were 93.9% versus 92.6%, 76.8% versus 72.8%, 86.5% versus 81.4%, and 73.2% versus 66.9%, respectively. The incidence rates of treatment-related adverse events with FosNTP versus FosAPR were 22.2% versus 25.4%, whereas adverse events or treatment-related adverse events relevant to injection site reactions were 11.0% versus 20.6% (P < .001) and 0.3% versus 3.6% (P < .001), respectively. CONCLUSION: FosNTP demonstrated noninferiority to FosAPR, with a favorable safety profile and lower risk for injection site reactions. Thus, FosNTP is valuable in the prophylaxis of acute, delayed, and beyond delayed chemotherapy-induced nausea and vomiting.

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.

A phase 1 pharmacokinetic study of oral NEPA, the fixed combination of netupitant and palonosetron, in Chinese healthy volunteers.

PURPOSE: Oral NEPA, the only fixed-combination antiemetic, is composed of the neurokinin-1 receptor antagonist netupitant (300 mg) and the 5-hydroxytryptamine-3 receptor antagonist palonosetron (0.50 mg). This study was conducted to evaluate the pharmacokinetic profile of netupitant and its main metabolites M1 and M3, and palonosetron in Chinese subjects. Oral NEPA tolerability and safety were also analyzed. METHODS: This was a single-center, single-dose phase 1 study in healthy, adult Chinese volunteers. Eligible subjects received oral NEPA, and blood samples were collected on day 1 predose and at various time points up until day 10 postdose. Pharmacokinetic parameters were analyzed using noncompartmental methods. For safety assessments, adverse events (AEs) were monitored during the study. RESULTS: In total 18 Chinese healthy volunteers received oral NEPA. Netupitant mean maximum plasma concentration (Cmax) [± standard deviation] of 698 ± 217 ng/mL was reached at 3-6 h, with a mean total exposure (AUC0-inf) of 22,000 ± 4410 h·ng/mL. For palonosetron, a mean Cmax of 1.8 ± 0.252 ng/mL was reached at 2-6 h postadministration, with a mean AUC0-inf of 81.0 ± 14.0 h·ng/mL. The most common treatment-related AEs in > 2 subjects were constipation (n = 9) and tiredness (n = 3). No severe AEs were observed, and no subject withdrew due to AEs. CONCLUSION: Following single-dose administration of oral NEPA in Chinese subjects, the pharmacokinetic profiles of the NEPA components were mostly similar to those reported previously in Caucasians. NEPA was well tolerated with a safety profile in line with that observed in pivotal trials in Caucasians.

Benefits and harms of NK1 R antagonists in pruritus: A systematic review and meta-analysis.

Accumulating evidence has showed the possibility of using NK1R antagonists for the treatment of chronic pruritus. However, the benefit and risk profile of NK1R antagonists-serlopitant and aprepitant for the treatment of pruritus remains unclear. To assess the efficacy and safety of NK1R antagonists-serlopitant and aprepitant in patients with pruritus based on analysis of clinical trials. The current systematic review and meta-analysis was performed according to PRISMA guidelines. A total of 10 randomized clinical trials including 631 patients were enrolled. Four randomized controlled trials investigated the comparative treatment effect of serlopitant on pruritus. Our results showed that serlopitant had reasonable anti-pruritic effectiveness in patients, with mild toxicities. The overall proportion of 4-point improvement of NRS and VAS in serlopitant-treatment group were both significantly higher relative to placebo group (OR 2.345, 95%CI 1.557 to 3.531, P < .001; OR 3.308, 95% CI 1.949 to 5.616, P < .001). Serlopitant treatment was also found to be associated with a significant reduction in NRS score as compared with placebo (SMD -0.381, 95%CI -0.599 to -0.164, P = .001). Six clinical trials reported the treatment effect of aprepitant on pruritus. The meta-analysis result of fixed-effect model showed that there was no significant difference between aprepitant and controlled treatment in terms of improved pruritus VAS score (SMD -0.088, 95%CI -0.384 to 0.207, P = .558). There is promising high-quality evidence regarding the efficacy of serlopitant on pruritus. More large-sample randomized controlled trials with appropriate treatment regimen are urgently needed to further evaluate the effectiveness of aprepitant in pruritus.

Clinical Applications of Substance P (Neurokinin-1 Receptor) Antagonist in Canine Medicine.

Substance P binds to the Neurokinin-1 (NK-1) receptors found in the emetic center of the central nervous system (CNS) to induce emesis. Maropitant is a selective NK-1 receptor antagonist that inhibits the binding of substance P to NK-1 receptors and is commonly used to prevent and treat vomiting in dogs. This review study aimed to discuss and analyze the therapeutic potential of substance P (Neurokinin-1 receptor) antagonist with a particular focus on the drug maropitant in canine medicine. A systematic literature review was performed to identify the existing literature on the subject during the past 20 years (2001-2021) using such databases as ScienceDirect, PubMed, Scopus, and Google Scholar. The initial search identified 173 articles; however, 41 articles were selected for further analysis, based on the specific inclusion and exclusion criteria. Studies have already confirmed the role of substance P and NK-1 receptors in central pain processing, intestinal smooth muscle contraction, vasodilation, and neurogenic inflammation. Maropitant is one of the most effective veterinary antiemetic drugs that work well against peripheral and central stimuli that trigger the vomiting center. It has been already demonstrated that the therapeutic efficacy of maropitant for managing acute vomiting in dogs is associated with pancreatitis, gastritis, and parvoviral enteritis. It can also prevent and treat chemotherapy-induced emesis and delay the signs of nausea and adverse gastrointestinal effects. Regarding the broad-spectrum antiemetic activity of maropitant, it can be recommended for managing uremic vomiting in dogs. In addition, it has also exhibited an anesthetic sparing effect since the dogs treated with maropitant require a slightly lower percentage of isoflurane as an inhalational anesthetic. The NK-1 receptors are also identified in different areas of the pain pathways. Therefore, NK-1 receptor antagonists might be effective for managing visceral pain. However, further studies are required to establish the broad therapeutic potential of NK-1 receptor antagonist drugs, such as maropitant in canine medicine. It has been shown that the pain associated with the subcutaneous administration of maropitant is due to metacresol, a preservative used in some formulations. Therefore, the side effects can be eliminated by developing novel maropitant formulations specifically for dogs.

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.

Serlopitant for psoriatic pruritus: A phase 2 randomized, double-blind, placebo-controlled clinical trial.

BACKGROUND: Pruritus, a common symptom of psoriasis, negatively affects quality of life; however, treatment of lesional skin does not consistently alleviate psoriatic itch. OBJECTIVE: To examine the effects of serlopitant, an oral, once-daily neurokinin 1 receptor antagonist, for treatment of psoriatic pruritus in a phase 2, randomized clinical trial (NCT03343639). METHODS: Patients (n = 204) were randomized to receive serlopitant, 5 mg, or placebo daily for 8 weeks. Eligible adult patients had plaque psoriasis for ≥6 months, plaques covering ≤10% of body surface area, pruritus for ≥4 weeks, and Worst Itch Numeric Rating Scale (WI-NRS) score ≥7 at the initial screening. RESULTS: Participants (54.2% women) had a mean age of 47.5 years and 85.2% were white. Mean baseline WI-NRS scores were 8.3 for serlopitant and 8.1 for placebo. The WI-NRS 4-point response rate at 8 weeks (primary end point) was 33.3% for serlopitant vs 21.1% for placebo (P = .028); at 4 weeks the rates were 20.8% for serlopitant vs 11.5% for placebo (P = .039). Treatment-related adverse events were reported for 4.9% of serlopitant-treated and 4.0% of placebo-treated patients. LIMITATIONS: This was a phase 2 study with a small study population. Patients with severe psoriasis were excluded. CONCLUSION: Serlopitant significantly reduced pruritus associated with mild to moderate psoriasis, supporting continued development of serlopitant for this patient population.

Peripheral neuropathy in non-Hodgkin's lymphoma patients receiving vincristine with and without aprepitant/fosaprepitant.

BACKGROUND: Peripheral neuropathy is a common treatment-related adverse effect associated with vincristine. Vincristine is a major CYP3A4 substrate and is often administered alongside the neurokinin-1 (NK-1) receptor antagonists, aprepitant or fosaprepitant, which are moderate CYP3A4 inhibitors. This inhibition may result in increased concentrations of vincristine and an increased incidence of toxicity. OBJECTIVE: The primary objective of this study was to investigate if there is a clinically significant drug interaction between vincristine and aprepitant or fosaprepitant resulting in early-onset peripheral neuropathy. The secondary objective of this study was to investigate the cumulative rate of chemotherapy-induced peripheral neuropathy (CIPN). METHODOLOGY: This was a single-centered, retrospective, cohort chart review. Patients receiving vincristine-based chemotherapy between 1 July 2010 through 30 June 2018 were identified and reviewed for concomitant use of aprepitant or fosaprepitant and incidence of neuropathy. Early-onset CIPN was defined as neuropathy onset during the first cycle of chemotherapy. RESULTS: A total of 115 subjects were retrospectively reviewed over the study period, of whom 71 were included in the aprepitant/fosaprepitant group and 44 were included in the group without a NK-1 receptor antagonist. Of the subjects who received aprepitant/fosaprepitant, 26.7% experienced early-onset peripheral neuropathy as compared to 22.7% in the group without a NK-1 receptor antagonist (P = 0.627). Overall, CIPN was higher in the group who received aprepitant/fosaprepitant compared to the group without (56% vs. 36%, P = 0.036). CONCLUSION: There appears to be an increased risk of CIPN with the concomitant use of vincristine and aprepitant or fosaprepitant.

Triple Negative Breast Cancer: How Neurokinin-1 Receptor Antagonists Could Be Used as a New Therapeutic Approach.

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females. BC cells not showing HER-2/Neu amplification and not expressing estrogen/ progesterone receptors are named triple-negative BC (TNBC) cells. TNBC represents 10-15% of all BC and is associated with an aggressive clinical course. TNBC patient prognosis, survival and response to current therapies are poor and for this reason, it is crucial to search for new therapeutic targets in TNBC to develop new therapeutic strategies. One of these targets is the neurokinin-1 receptor (NK-1R). It is well known that the substance P (SP)/NK-1R system is involved in cancer progression. TNBC cells overexpress the NK-1R and, after binding to this receptor, SP promotes the proliferation/ migration of TNBC cells. Non-peptide NK-1R antagonists (e.g., aprepitant) are known to exert, via the NK-1R, an antitumor action; TNBC cells die by apoptosis. In this review, we update the data on a promising therapeutic innovation: the use of NK-1R antagonists for the treatment of TNBC patients.

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.

The safety of rolapitant for the treatment of nausea and vomiting associated with chemotherapy.

Introduction: Chemotherapy-induced nausea and vomiting is a significant clinical issue that affects patients' quality of life as well as treatment decisions. Significant improvements in the control of chemotherapy-induced nausea and vomiting have occurred in the past 15 years with the introduction of new antiemetic agents 5-HT3, receptor antagonists, neurokinin-1 receptor antagonists, and olanzapine. Oral (aprepitant, 2003; netupitant, 2014; rolapitant, 2015) neurokinin-1 receptor antagonists have been developed along with intravenous formulations (fosaprepitant, NEPA, rolapitant, HTX-019) for the prevention of chemotherapy-induced nausea and vomiting.Areas covered: This review presents a description of the safety and efficacy of rolapitant along with a comparison to the other oral and intravenous formulations of the neurokinin-1 receptor antagonists.Expert opinion: Oral rolapitant has been demonstrated in clinical trials to be safe and effective in controlling chemotherapy-induced nausea and vomiting in patients receiving moderately and highly emetogenic chemotherapy. Rolapitant has a longer half-life (180 h) than other commercially available NK-1 receptor antagonists and does not induce or inhibit CYP34A, unlike the other NK-1 receptor antagonists. Future studies may determine if these may be important clinical issues.

Pharmacokinetics of maropitant citrate in New Zealand White rabbits (Oryctolagus cuniculus).

OBJECTIVE: To determine the pharmacokinetics and adverse effects of maropitant citrate after IV and SC administration to New Zealand White rabbits (Oryctolagus cuniculus). ANIMALS: 11 sexually intact (3 males and 8 females) adult rabbits. PROCEDURES: Each rabbit received maropitant citrate (1 mg/kg) IV or SC. Blood samples were collected at 9 (SC) or 10 (IV) time points over 48 hours. After a 2-week washout period, rabbits received maropitant by the alternate administration route. Pharmacokinetic parameters were calculated. Body weight, food and water consumption, injection site, mentation, and urine and fecal output were monitored. RESULTS: Mean ± SD maximum concentration after SC administration was 14.4 ± 10.9 ng/mL and was detected at 1.25 ± 0.89 hours. Terminal half-life after IV and SC administration was 10.4 ± 1.6 hours and 13.1 ± 2.44 hours, respectively. Bioavailability after SC administration was 58.9 ± 13.3%. Plasma concentration at 24 hours was 2.87 ± 1.69 ng/mL after IV administration and 3.4 ± 1.2 ng/mL after SC administration. Four rabbits developed local dermal reactions at the injection site after SC injection. Increased fecal production was detected on the day of treatment and 1 day after treatment. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma concentrations of rabbits 24 hours after SC and IV administration of maropitant citrate (1 mg/kg) were similar to those of dogs at 24 hours. Reactions at the SC injection site were the most common adverse effect detected. Increased fecal output may suggest an effect on gastrointestinal motility. Additional pharmacodynamic and multidose studies are needed.

The NK1 receptor antagonist serlopitant for treatment of chronic pruritus.

Introduction: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK1) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin. Areas covered: This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK1 receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies. Expert opinion: There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.

Neurokinin-1 receptor antagonists: review of their role for the prevention of chemotherapy-induced nausea and vomiting in adults.

Introduction: The addition of neurokinin-1 receptor antagonists (NK1RAs) to standard prophylaxis of 5-hydroxytryptamine-3 RA (5-HT3RA) plus dexamethasone more effectively prevents chemotherapy-induced nausea and vomiting (CINV) associated with highly and moderately emetogenic chemotherapy. Areas covered: This review presents the evidence base for the use of oral and intravenous (IV) NK1RAs, focusing on the pharmacologic and clinical properties as a class, and highlighting differences between agents. A PubMed literature search was conducted from 2000 to 2018. Expert opinion: Adherence to international antiemetic guidelines remains a clinical challenge. Strategies to simplify antiemetic regimens and facilitate their administration may improve compliance and treatment outcomes. The use of fixed-combination antiemetics offers clinical utility, in combining an NK1RA with a 5-HT3RA in a single oral dose. The use of long-lasting NK1RAs and administering CINV prophylaxis closer to the time of chemotherapy may also assist with guideline and treatment compliance, diminishing the need for home-based administration, and potentially reducing resource utilization. The availability of IV and oral formulations of NK1RAs and NK1RA-5-HT3RA fixed combinations offers further utility, particularly for those patients unsuited for oral administration. However, safety considerations with respect to injection site toxicity and hypersensitivity reactions of the new NK1RA IV formulations deserve close attention.

Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial.

BACKGROUND: Anecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN). OBJECTIVE: This study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN. METHODS: In this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6 weeks received serlopitant, 5 mg, or placebo orally once daily for 8 weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8. RESULTS: Average itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was -1.0 at week 4 (P = .02) and -1.7 at week 8 (P < .001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (-0.9 [P = .011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue. LIMITATIONS: The 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions. CONCLUSIONS: Serlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated.

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).