Rolapitant
Regulatory sources consulted
Approved indications
- With other antiemetics, prevention of delayed nausea and vomiting from emetogenic chemotherapy in adults.
Contraindications
Absolute
- Concomitant use of narrow-therapeutic-index CYP2D6 substrates such as pimozide or thioridazine.
- Use in children younger than 2 years because of the risk of serious or fatal adverse reactions.
Clinical warnings
- Major warning · It is contraindicated with narrow-therapeutic-index CYP2D6 substrates such as pimozide or thioridazine; inhibition can persist for at least 28 days. — FDA label
Drug interactions
- HighBCRP substrates (for example, rosuvastatin)
Mechanism: Rolapitant inhibits BCRP and may increase substrate exposure.
Recommendation: The treating team should review the substrate label, limit or adjust its dose when appropriate, and monitor for adverse reactions.
FDA label
- HighP-gp substrates (for example, digoxin)
Mechanism: Rolapitant inhibits P-gp and may increase substrate exposure.
Recommendation: The treating team should monitor substrate concentrations and toxicity and adjust management according to its label.
FDA label
- ModerateWarfarin
Mechanism: Coadministration may alter the anticoagulant effect.
Recommendation: The treating team should monitor INR and adjust anticoagulation if needed.
FDA label
- HighStrong CYP3A4 inducers
Mechanism: Strong CYP3A4 inducers significantly reduce rolapitant exposure and may reduce its effectiveness.
Recommendation: Avoid the combination; the treating team should select a compatible alternative.
FDA label
Recent literature (PubMed)
About 70% to 80% of adults with cancer experience chemotherapy-induced nausea and vomiting (CINV). CINV remains one of the most distressing symptoms associated with cancer therapy and is associated with decreased adherence to chemotherapy. Combining 5-hydroxytryptamine-3 (5-HT₃) receptor antagonists with corticosteroids or additionally with neurokinin-1 (NK₁) receptor antagonists is effective in preventing CINV among adults receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). Various treatment options are available, but direct head-to-head comparisons do not allow comparison of all treatments versus another. OBJECTIVES: • In adults with solid cancer or haematological malignancy receiving HEC - To compare the effects of antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids on prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting in network meta-analysis (NMA) - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy • In adults with solid cancer or haematological malignancy receiving MEC - To compare whether antiemetic treatment combinations including NK₁ receptor antagonists, 5-HT₃ receptor antagonists, and corticosteroids are superior for prevention of acute phase (Day 1), delayed phase (Days 2 to 5), and overall (Days 1 to 5) chemotherapy-induced nausea and vomiting to treatment combinations including 5-HT₃ receptor antagonists and corticosteroids solely, in network meta-analysis - To generate a clinically meaningful treatment ranking according to treatment safety and efficacy SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, conference proceedings, and study registries from 1988 to February 2021 for randomised controlled trials (RCTs). We included RCTs including adults with any cancer receiving HEC or MEC (according to the latest definition)
This phase I trial aimed to assess the pharmacokinetics (PK), safety, and preliminary efficacy of a single dose of HR20013 (mixed formulation of fosrolapitant and palonosetron) plus dexamethasone in patients with malignant solid tumors. Solid tumor patients who were naive to cisplatin-based chemotherapy and scheduled to receive the single-day cisplatin-based chemotherapy were enrolled. Patients would receive a single intravenous infusion of HR20013 (Day 1) before cisplatin-based chemotherapy, alongside oral dexamethasone (Day 1, 12 mg, once a day; Day 2-4, 3.75 mg, twice a day). Primary endpoints were PK parameters of fosrolapitant, rolapitant, M19 (a major active metabolite of rolapitant), palonosetron, and dexamethasone. Twenty-four patients were enrolled, and 22 received study treatment. Fosrolapitant reached maximum plasma concentration (Cmax) immediately at the end of the infusion of HR20013 (1 h), followed by a short terminal phase, and it was completely hydrolyzed into rolapitant. Mean elimination half-lives of rolapitant and palonosetron were 188.2 and 51.5 h, respectively. M19 reached Cmax at approximately 166.2 h. After a single oral administration of dexamethasone at 12 mg, when combined with HR20013, dexamethasone reached Cmax at approximately 1.5 h, with a mean Cmax of 106.0 ng/mL. Treatment-related adverse events occurred in 54.5% of patients, with constipation (22.7%), increased blood pressure (18.2%), abdominal distension (13.6%), injection site reaction (9.1%), and increased neutrophil count (9.1%) being most common. Complete response rates (no emesis/rescue therapy) were 90.9% at the overall phase (0-120 h) and 86.4% at the beyond delayed phase (120-168 h). HR20013 plus dexamethasone had a favorable PK profile, manageable safety, and durable antiemetic efficacy. ClinicalTrials.gov, NCT05465681.
OTUD3 (Ovarian Tumor Domain-Containing Protein 3), a deubiquitinating enzyme, has emerged as a pivotal and context-dependent regulator in cancer pathogenesis, exhibiting a striking functional duality as either a tumor suppressor or oncoprotein across different cancer types. Acting as a dual regulator, it influences key cellular processes-including proliferation, apoptosis, immune evasion, and metabolic reprogramming-by stabilizing specific substrates such as PTEN, p53, GRP78, YY1, and PD-L1. Its role extends to modulating inflammatory signaling, antiviral immunity, and metabolic homeostasis, highlighting its broad functional versatility. The development of OTUD3-targeted inhibitors like Rolapitant, Rupatadine, and OTUDin3 shows promise in preclinical models, particularly in combination with immunotherapy. However, its tissue-specific duality poses both challenges and opportunities for therapeutic intervention. Further research is needed to elucidate OTUD3's mechanistic networks and advance its clinical translation as a prognostic biomarker and therapeutic target in precision oncology.