Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC)

Rapoport, Bernardo; Chua, Daniel T.T.; Poma, Allen; Arora, Siddharth; Wang, Yan; Fein, Luis

doi:10.1007/s00520-015-2738-1

Cited by 61 publications

(82 citation statements)

References 31 publications

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“…The phase II cisplatin-based HEC (NCT00394966) [16], phase III cisplatin-based HEC-1 (NCT01499849) and cisplatin-based HEC-2 (NCT01500213) [17], and phase III moderately emetogenic chemotherapy or AC-based chemotherapy (NCT01500226) [18] randomized, double-blind, parallel-group trials enrolled patients scheduled to receive their first chemotherapy treatment. Eligibility criteria for these studies have been described [16–18] and are included in the supplementary material, available at Annals of Oncology online.…”

Section: Methodsmentioning

confidence: 99%

“…In randomized phase II and III trials, a single 180-mg oral dose of rolapitant with a 5-HT 3 RA and dexamethasone regimen on the same day as chemotherapy provided superior protection against nausea and/or vomiting on days 2–5 after chemotherapy [16–18]. The safety profile of rolapitant was consistent across studies, with a low incidence of treatment-related AEs generally comparable to that observed in control arms [16–18]. Unlike other approved oral NK 1 RAs [19], rolapitant does not induce or inhibit CYP3A4 [20, 21].…”

Section: Introductionmentioning

confidence: 99%

“…Here, we report an integrated analysis of safety using pooled data from the phase II and III rolapitant studies [16–18] to assess possible safety signals in patients administered concomitant drugs that are substrates of CYP2D6 or BCRP.…”

Section: Introductionmentioning

confidence: 99%

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Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials: an assessment of CYP2D6 or BCRP inhibition by rolapitant

et al. 2017

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BackgroundRolapitant, a long-acting neurokinin (NK)1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug–drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events (AEs) by use versus non-use of drug substrates of CYP2D6 or BCRP.Patients and methodsPatients were randomized to receive either 180 mg oral rolapitant or placebo ∼1–2 h before chemotherapy in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Data for treatment-emergent AEs (TEAEs) and treatment-emergent serious AEs (TESAEs) during cycle 1 were pooled across the four studies and summarized in the overall population and by concomitant use/non-use of CYP2D6 or BCRP substrate drugs.ResultsIn the integrated safety population, 828 of 1294 patients (64%) in the rolapitant group and 840 of 1301 patients (65%) in the control group experienced at least one TEAE. Frequencies of common TEAEs were similar in the rolapitant and control populations. Overall, 53% of patients received CYP2D6 substrate drugs, none of which had a narrow therapeutic index (like thioridazine or pimozide), and 63% received BCRP substrate drugs. When grouped by concomitant use versus non-use of CYP2D6 or BCRP substrate drugs, TEAEs and TESAEs occurred with similar frequency in the rolapitant and control populations.ConclusionsThe results of this study support the safety of rolapitant as part of an antiemetic triple-drug regimen in patients receiving emetogenic chemotherapy, including those administered concomitant medications that are substrates of CYP2D6 or BCRP, such as ondansetron, docetaxel, or irinotecan.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials: an assessment of CYP2D6 or BCRP inhibition by rolapitant

et al. 2017

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“…It exhibits the longest half life (180 hours) in this drug class and occupies CNS NK 1 receptors for >5 days (34). In a phase 2 trial, rolapitant produced significantly better complete responses in CINV versus a regimen of ondansetron plus dexamethasone (35). In three phase 3 investigations, this agent elicited higher responses particularly in the delayed phase of CINV than control groups who received a 5-HT 3 antagonist and corticosteroid (36).…”

Section: Medications Used To Treat Nausea and Vomitingmentioning

confidence: 99%

Newest Drugs for Chronic Unexplained Nausea and Vomiting

Hasler

2016

Curr Treat Options Gastro

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OPINION STATEMENT Chronic unexplained nausea and vomiting (CUNV) refers to a symptom complex defined by nausea and/or vomiting with normal diagnostic testing, including anatomic assessments (including upper endoscopy) and measures of upper gut function (e.g. gastric emptying testing). Nausea and vomiting in this condition are postulated to result from aberrant peripheral or central neurohumoral activity. A substantial subset of patients satisfies this diagnosis as more than half of individuals referred for scintigraphic testing exhibit normal gastric emptying rates. No randomized, placebo-controlled trials of any medication treatment have been performed in CUNV. However, agents with potential therapeutic benefit in CUNV include antiemetic drugs, neuromodulatory treatments which are proposed to act by reducing gastric sensitivity, and medications with prokinetic action to stimulate upper gut propulsion. Recently approved drugs with antiemetic capability include serotonin antagonists with novel modes of delivery and neurokinin antagonists with or without additional serotonergic blocking capabilities. Existing neuroleptics and pain modifying neuromodulatory therapies with fortuitous antiemetic benefits are being considered for their benefits in this disorder. Furthermore, current investigations will define potential therapeutic actions of agents that stimulate gastric emptying via action on gastroduodenal serotonin, motilin, and ghrelin receptors. This current research may broaden the treatment options for refractory cases of unexplained nausea and vomiting.

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“…Patients in the rolapitant group had a significantly higher CR rate in the acute, delayed and overall phases compared to granisetron and dexamethasone plus placebo. Moreover, the rolapitant group achieved higher rates of complete protection in both delayed and overall phases (32,33).…”

Section: Neurokinin 1 Receptor Antagonists: the New Drugsmentioning

confidence: 99%

Chemotherapy-induced nausea and vomiting: update and future options

Pacetti¹

2014

RIO

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Even though great progress has been made in the control of chemotherapy-induced nausea and vomiting (CINV), more research is still needed. The use of serotonin-5HT3 receptors antagonists(5-HT3RAs) plus dexamethasone has improve the control of CINV and palonosetron, a second-generation 5-HT3RA, appears to be the most effective agents in its class. Aprepitant, the first neurokinin 1 receptor antagonist (NK1RA) has been used effectively as an additive agent to the 5-HT3RAs while rolapitant and netupitant are being evaluated in phase III clinical trials. This review is an update of the current schedules in preventing CINV and considers possible future strategies.KEY WORDS: palonosetron and CINV, NEPA, NK 1 receptor antagonists.

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Study of rolapitant, a novel, long-acting, NK-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting (CINV) due to highly emetogenic chemotherapy (HEC)

Abstract: All doses of rolapitant were well tolerated and showed greater CR rates than active control. Rolapitant 180 mg demonstrated significant clinical efficacy for preventing CINV in the overall, delayed, and acute phases for patients receiving HEC.

Cited by 61 publications

References 31 publications

Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials: an assessment of CYP2D6 or BCRP inhibition by rolapitant

Integrated safety analysis of rolapitant with coadministered drugs from phase II/III trials: an assessment of CYP2D6 or BCRP inhibition by rolapitant

Newest Drugs for Chronic Unexplained Nausea and Vomiting

Chemotherapy-induced nausea and vomiting: update and future options

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