Pharmacokinetics, safety, and efficacy of mixed formulation of fosrolapitant and palonosetron (HR20013) in combination with dexamethasone in patients with solid tumors scheduled for highly emetogenic cisplatin-based chemotherapy: a phase I trial.
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Abstract
Background: 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.
Methods: 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.
Results: 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).
Conclusions: HR20013 plus dexamethasone had a favorable PK profile, manageable safety, and durable antiemetic efficacy.
期刊介绍：
BMC Medicine is an open access, transparent peer-reviewed general medical journal. It is the flagship journal of the BMC series and publishes outstanding and influential research in various areas including clinical practice, translational medicine, medical and health advances, public health, global health, policy, and general topics of interest to the biomedical and sociomedical professional communities. In addition to research articles, the journal also publishes stimulating debates, reviews, unique forum articles, and concise tutorials. All articles published in BMC Medicine are included in various databases such as Biological Abstracts, BIOSIS, CAS, Citebase, Current contents, DOAJ, Embase, MEDLINE, PubMed, Science Citation Index Expanded, OAIster, SCImago, Scopus, SOCOLAR, and Zetoc.
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