Rolapitant 90mg tablets

Rolapitant is a highly selective neurokinin-1 receptor antagonist, orally administered for a single dose of 180 mg before chemotherapy with granisetron D1, dexamethasone 8 mg BID on day 2-4. It has a unique pharmacological characteristic of a long plasma half-life (between 163 and 183 hours); this long half-life makes a single use sufficient to cover the delayed emesis risk period. No major drug-drug interactions between rolapitant and dexamethasone or other cytochrome P450 inducers or inhibitors were observed. The clinical efficacy of rolapitant was studied in two phase III trials in highly emetogenic chemotherapy and in one clinical trial in moderately emetogenic chemotherapy. The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 hours after chemotherapy). In comparison to granisetron (10 μg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2-4 and placebo, rolapitant showed superior efficacy in the control of delayed and overall emesis. This review aims at revising the pharmacological characteristics of rolapitant, offering an updated review of the available clinical efficacy and safety data of rolapitant in different clinical settings, highlighting the place of rolapitant in the management of chemotherapy-induced nausea and vomiting (CINV) among currently available guidelines, and exploring the future directions of CINV management.

Abstract licence: CC BY-NC

PurposePrevention of chemotherapy induced nausea and vomiting (CINV) is an integral aspect of hematopoietic stem cell transplant (HCT) due to the emetogenicity of the conditioning regimen. Post-transplant cyclophosphamide (PTCy) is a highly emetogenic agent, emerging as a graft versus host disease (GVHD) prophylactic regimen for matched related (MRD) and unrelated donors (MUD). The purpose was to evaluate episodes of nausea, vomiting, and antiemetic breakthrough medication utilization when ondansetron plus rolapitant was given for CINV prophylaxis during PTCy administration following triplet or quadruplet CINV prophylaxis with the conditioning regimen.MethodsThis was a single center, retrospective review of patients from July 2017 to August 2019 undergoing MRD or MUD stem cell transplant. Episodes of nausea and emesis were extracted by review of nursing flowsheets in the electronic medical record. Additionally, medication records were reviewed for the administration of breakthrough antiemetics, including dronabinol, ondansetron, prochlorperazine, scopolamine, and trimethobenzamide. Patients were evaluated each day chemotherapy was administered (acute phase) plus an additional three days (delayed phase) after completion of the conditioning regimen and PTCy.ResultsThe analysis included 33 patients who were predominantly male (66.6%) with median age of 58 years. Thirty patients (90%) received their graft from a MUD. Indications for HCT, as well as the conditioning regimens, are listed in Fig 1. Rates of documented episodes of nausea, vomiting, and breakthrough antiemetic utilization are listed in Table 1. Breakthrough medications were utilized by 30 patients (90%). A total of 173 doses were administered with 68 doses (40%) given during the conditioning regimen and 105 doses (60%) during PTCy (Fig 2). Ondansetron was the most commonly used antiemetic with 105 doses (61%) followed by prochlorperazine with 68 doses (39%).ConclusionsPTCy is highly emetogenic GVHD prophylaxis regimen requiring utilization of breakthrough antiemetics despite prophylaxis with ondansetron plus rolapitant. This evaluation demonstrates CINV may be present when PTCy is administered for MUD and MRD grafts, despite quadruplet or triplet antiemetic prophylaxis with the conditioning regimen. PTCy warrants additional antiemetic prophylaxis to minimize the use of breakthrough antiemetics. Additionally, nausea and vomiting were not well documented in the medical record limiting analysis of clinical episodes. Future studies are needed to identify strategies to improve CINV protection when utilizing PTCy for MUD and MRD HCT. Prevention of chemotherapy induced nausea and vomiting (CINV) is an integral aspect of hematopoietic stem cell transplant (HCT) due to the emetogenicity of the conditioning regimen. Post-transplant cyclophosphamide (PTCy) is a highly emetogenic agent, emerging as a graft versus host disease (GVHD) prophylactic regimen for matched related (MRD) and unrelated donors (MUD). The purpose was to evaluate episodes of nausea, vomiting, and antiemetic breakthrough medication utilization when ondansetron plus rolapitant was given for CINV prophylaxis during PTCy administration following triplet or quadruplet CINV prophylaxis with the conditioning regimen. This was a single center, retrospective review of patients from July 2017 to August 2019 undergoing MRD or MUD stem cell transplant. Episodes of nausea and emesis were extracted by review of nursing flowsheets in the electronic medical record. Additionally, medication records were reviewed for the administration of breakthrough antiemetics, including dronabinol, ondansetron, prochlorperazine, scopolamine, and trimethobenzamide. Patients were evaluated each day chemotherapy was administered (acute phase) plus an additional three days (delayed phase) after completion of the conditioning regimen and PTCy. The analysis included 33 patients who were predominantly male (66.6%) with median age of 58 years. Thirty patients (90%) received their graft from a MUD. Indications for HCT, as well as the conditioning regimens, are listed in Fig 1. Rates of documented episodes of nausea, vomiting, and breakthrough antiemetic utilization are listed in Table 1. Breakthrough medications were utilized by 30 patients (90%). A total of 173 doses were administered with 68 doses (40%) given during the conditioning regimen and 105 doses (60%) during PTCy (Fig 2). Ondansetron was the most commonly used antiemetic with 105 doses (61%) followed by prochlorperazine with 68 doses (39%). PTCy is highly emetogenic GVHD prophylaxis regimen requiring utilization of breakthrough antiemetics despite prophylaxis with ondansetron plus rolapitant. This evaluation demonstrates CINV may be present when PTCy is administered for MUD and MRD grafts, despite quadruplet or triplet antiemetic prophylaxis with the conditioning regimen. PTCy warrants additional antiemetic prophylaxis to minimize the use of breakthrough antiemetics. Additionally, nausea and vomiting were not well documented in the medical record limiting analysis of clinical episodes. Future studies are needed to identify strategies to improve CINV protection when utilizing PTCy for MUD and MRD HCT.

Abstract licence: CC BY-NC-ND

BACKGROUND: Rolapitant, a novel neurokinin-1 receptor antagonist, provided effective protection against chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase 3 trial of patients receiving moderately emetogenic chemotherapy or an anthracycline and cyclophosphamide regimen. The current analysis explored the efficacy and safety of rolapitant in preventing CINV in a subgroup of patients receiving carboplatin. METHODS: Patients were randomized 1:1 to receive oral rolapitant (180 mg) or a placebo 1 to 2 hours before chemotherapy administration; all patients received oral granisetron (2 mg) on days 1 to 3 and oral dexamethasone (20 mg) on day 1. A post hoc analysis examined the subgroup of patients receiving carboplatin in cycle 1. The efficacy endpoints were as follows: complete response (CR), no emesis, no nausea, no significant nausea, complete protection, time to first emesis or use of rescue medication, and no impact on daily life. RESULTS: In the subgroup administered carboplatin-based chemotherapy (n = 401), a significantly higher proportion of patients in the rolapitant group versus the control group achieved a CR in the overall phase (0-120 hours; 80.2% vs 64.6%; P < .001) and in the delayed phase (>24-120 hours; 82.3% vs 65.6%; P < .001) after chemotherapy administration. Superior responses were also observed by the measures of no emesis, no nausea, and complete protection in the overall and delayed phases and by the time to first emesis or use of rescue medication. The incidence of treatment-emergent adverse events was similar for the rolapitant and control groups. CONCLUSIONS: Rolapitant provided superior CINV protection to patients receiving carboplatin-based chemotherapy in comparison with the control. These results support rolapitant use as part of the antiemetic regimen in carboplatin-treated patients. Cancer 2016;122:2418-2425. © 2016 American Cancer Society.

Abstract licence: CC BY-NC

BACKGROUND: Lung cancer is cancer with the highest morbidity and mortality in the world and poses a serious threat to human health. Therefore, discovering new treatments is urgently needed to improve lung cancer prognosis. Small molecule inhibitors targeting the ubiquitin-proteasome system have achieved great success, in which deubiquitinase inhibitors have broad clinical applications. The deubiquitylase OTUD3 was reported to promote lung tumorigenesis by stabilizing oncoprotein GRP78, implying that inhibition of OTUD3 may be a therapeutic strategy for lung cancer. RESULTS: In this study, we identified a small molecule inhibitor of OTUD3, Rolapitant, by computer-aided virtual screening and biological experimental verification from FDA-approved drugs library. Rolapitant inhibited the proliferation of lung cancer cells by inhibiting deubiquitinating activity of OTUD3. Quantitative proteomic profiling indicated that Rolapitant significantly upregulated the expression of death receptor 5 (DR5). Rolapitant also promoted lung cancer cell apoptosis through upregulating cell surface expression of DR5 and enhanced TRAIL-induced apoptosis. Mechanistically, Rolapitant directly targeted the OTUD3-GRP78 axis to trigger endoplasmic reticulum (ER) stress-C/EBP homologous protein (CHOP)-DR5 signaling, sensitizing lung cancer cells to TRAIL-induced apoptosis. In the vivo assays, Rolapitant suppressed the growth of lung cancer xenografts in immunocompromised mice at suitable dosages without apparent toxicity. CONCLUSION: In summary, the present study identifies Rolapitant as a novel inhibitor of deubiquitinase OTUD3 and establishes that the OTUD3-GRP78 axis is a potential therapeutic target for lung cancer.

Abstract licence: CC BY