aprepitant and casopitant

The addition of neurokinin-1 receptor (NK1R) antagonists to antiemetic regimens has substantially reduced chemotherapy-induced nausea and vomiting (CINV). We sought to systematically review the overall impact of NK1R antagonists on CINV prevention.. We systematically searched the MEDLINE, EMBASE, and CENTRAL databases, and meeting proceedings for randomized controlled trials (RCTs) that evaluated NK1R antagonists plus standard antiemetic therapy for CINV prevention. Complete response (CR) to therapy was defined as the absence of emesis and the absence of rescue therapy. The endpoints were defined as CR in the overall phase (during the first 120 hours of chemotherapy), CR in the acute phase (first 24 hours), and the delayed phase (24-120 hours) after chemotherapy, nausea, and toxicity. Subgroup analyses evaluated the type of NK1R antagonist used, the emetogenic potential of the chemotherapy regimen, and prolonged use of 5-HT3 (serotonin) receptor antagonists, a class of standard antiemetic agents. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates and publication bias were two-sided.. Seventeen trials (8740 patients) were included in this analysis. NK1R antagonists increased the CR rate in the overall phase from 54% to 72% (OR = 0.51, 95% CI = 0.46 to 0.57, P < .001). CR and nausea were improved in all phases and subgroups. The expected side effects from NK1R antagonists did not statistically significantly differ from previous reports; however, this analysis suggests that the incidence of severe infection increased from 2% to 6% in the NK1R antagonist group (three RCTs with a total of 1480 patients; OR = 3.10; 95% CI = 1.69 to 5.67, P < .001).. NK1R antagonists increased CINV control in the acute, delayed, and overall phases. They are effective for both moderately and highly emetogenic chemotherapy regimens. Their use might be associated with increased infection rates; however, additional appraisal of specific data from RCTs is needed.

Topics: Antiemetics; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Confidence Intervals; Humans; Infections; Morpholines; Nausea; Neoplasms; Neurokinin-1 Receptor Antagonists; Odds Ratio; Piperazines; Piperidines; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists; Vomiting

Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles, and patient risk factors significantly influence CINV. 5-hydroxytryptamine-3 (5-HT(3)) receptor antagonists plus dexamethasone have significantly improved the control of acute CINV, but delayed CINV remains a significant clinical problem. Two new agents, palonosetron and aprepitant, have been approved for the prevention of both acute and delayed CINV. Palonosetron is a second-generation 5-HT(3) receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT(3) receptor antagonists. Aprepitant is the first agent available in the new drug class of neurokinin-1 (NK-1) receptor antagonists. Casopitant is another NK-1 receptor antagonist that is under review by the FDA after recent completion of Phase III clinical trials. The introduction of these new agents has generated revised antiemetic guidelines for the prevention of CINV. Future studies may consider the use of palonosetron, aprepitant and casopitant with other antiemetic agents (olanzapine, gabapentin, cannabinoids) in moderately and highly emetogenic chemotherapy, as well as in the clinical settings of multiple-day chemotherapy and bone marrow transplantation.

Topics: Antiemetics; Antineoplastic Agents; Aprepitant; Clinical Trials, Phase III as Topic; Humans; Isoquinolines; Morpholines; Nausea; Palonosetron; Piperazines; Piperidines; Quinuclidines; Serotonin Antagonists; Vomiting

Tachykinins (TKs) are small peptides widely distributed in the central and peripheral nervous systems where they act as neurotransmitters. Potent and selective TKs antagonists have been developed in the last 20 years and many efforts have been made to prove their efficacy in the treatment of various diseases. Herein the most prominent results in the clinical development are reported and discussed. For aprepitant, the only compound of this class to have been launched to date, results of clinical studies and postmarketing cost-effectiveness data for the treatment of chemotherapy-induced emesis are discussed. The field is still well active, as currently proof-of-concept studies for indications initially missed (i.e., depression) are ongoing and new targets are under investigation.

Topics: Antiemetics; Aprepitant; Asthma; Clinical Trials as Topic; Gastrointestinal Diseases; Humans; Mental Disorders; Morpholines; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Receptors, Neurokinin-2; Receptors, Neurokinin-3; Sleep Initiation and Maintenance Disorders

The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.

Topics: Animals; Antidepressive Agents; Behavior, Animal; Bridged Bicyclo Compounds, Heterocyclic; CHO Cells; Cricetinae; Cricetulus; Dogs; Female; Gerbillinae; Half-Life; Humans; Male; Models, Molecular; Molecular Conformation; Neurokinin-1 Receptor Antagonists; Piperazines; Piperidines; Protein Binding; Rats; Receptors, Neurokinin-1