| Reference | [1]. Drug Metab Dispos. 2019 Jun;47(6):567-573. doi: 10.1124/dmd.118.085928. Epub 2019 Apr 5.<br />
Rolapitant Is a Reversible Inhibitor of CYP2D6.<br />
Glass SM(1), Leddy SM(1), Orwin MC(1), Miller GP(1), Furge KA(1), Furge LL(2).<br />
Author information: (1)Department of Chemistry, Kalamazoo College, Kalamazoo, Michigan. (2)Department of Chemistry, Kalamazoo College, Kalamazoo, Michigan [email protected].<br />
Rolapitant [(Varubi), 5S,8S)-8-[[(1R)-1-[3,5 bis(trifluoromethyl phenyl]ethoxy]methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one] is a high-affinity NK1 receptor antagonist that was approved in September 2015 as a treatment for nausea and vomiting caused by chemotherapy. In vivo rolapitant moderately inhibits CYP2D6 for at least 7 days after one 180 mg dose. Due to the long inhibition time, we investigated rolapitant as a possible mechanism-based inactivator of CYP2D6. Rolapitant docked in the active site of CYP2D6 and displayed type I binding to CYP2D6 with a K s value of 1.2 ± 0.4 µM. However, in NADPH-, time-, and concentration-dependent assays of CYP2D6 activity, no evidence for mechanism-based inactivation and no metabolites of rolapitant were observed. Stopped-flow binding studies yielded a kon /koff (K d) value of 6.2 µM. The IC50 value for rolapitant inhibition of CYP2D6 activity was 24 µM, suggesting that inhibition is not due to tight binding of rolapitant to CYP2D6. By Lineweaver-Burk analysis, rolapitant behaved as a mixed, reversible inhibitor. The K i values of 20 and 34 µM were determined by Dixon analysis, with bufuralol and dextromethorphan as reporter substrates, respectively, and drug-drug interaction modeling did not predict the reported in vivo inhibition. The interaction of rolapitant with CYP2D6 was also examined in 1 microsecond molecular dynamics simulations. Rolapitant adopted multiple low-energy binding conformations near the active site, but at distances not consistent with metabolism. Given these findings, we do not see evidence that rolapitant is a mechanism-based inactivator. Moreover, the reversible inhibition of CYP2D6 by rolapitant may not fully account for the moderate inhibition described in vivo.<br />
DOI: 10.1124/dmd.118.085928 PMCID: PMC6505376 PMID: 30952677 [Indexed for MEDLINE]<br />
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[2]. Drugs. 2015 Nov;75(16):1941-5. doi: 10.1007/s40265-015-0485-8.<br />
Rolapitant: first global approval.<br />
Syed YY(1).<br />
Author information: (1)Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand. [email protected].<br />
Rolapitant (Varubi™) is an orally active neurokinin-1 receptor antagonist developed by TESARO and approved in the USA for use in combination with other antiemetic agents for the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in adults. Unlike other approved agents in this class, rolapitant does not interact with cytochrome P450 (CYP) enzyme CYP3A4. It also has a long elimination half-life which means that a single dose could prevent CINV during the entire at-risk period (0-120 h). An intravenous formulation of rolapitant is under clinical development in the USA. Phase II development of rolapitant in postoperative nausea and vomiting, and cough appears to have been discontinued. This article summarizes the milestones in the development of rolapitant leading to the first approval for the prevention of CINV.<br />
DOI: 10.1007/s40265-015-0485-8 PMID: 26467681 [Indexed for MEDLINE]<br />
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[3]. Drugs. 2017 Oct;77(15):1687-1694. doi: 10.1007/s40265-017-0816-z.<br />
Rolapitant: A Review in Chemotherapy-Induced Nausea and Vomiting.<br />
Heo YA(1), Deeks ED(2).<br />
Author information: (1)Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand. [email protected]. (2)Springer, Private Bag 65901, Mairangi Bay, Auckland, 0754, New Zealand.<br />
Oral rolapitant (Varubi™; Varuby®), a long-acting neurokinin-1 (NK1) receptor antagonist (RA), is indicated in the USA and EU as part of an antiemetic regimen to prevent delayed chemotherapy-induced nausea and vomiting (CINV) in adults receiving highly or moderately emetogenic chemotherapy (HEC or MEC). In randomized, phase III trials, a single oral dose of rolapitant 180 mg was effective in preventing delayed CINV compared with placebo, when each was used in combination with a 5-HT3 RA plus dexamethasone, in adults receiving their first course of HEC or MEC. The benefits of rolapitant were maintained over multiple cycles of chemotherapy. The tolerability profile of rolapitant is similar to that of placebo and consistent with that of other NK1 RAs. However, rolapitant differs from other existing NK1 RAs in that it does not interact with CYP3A4, thereby negating the need for dexamethasone dose adjustments and potentially making rolapitant a more suitable option for patients receiving CYP3A4 substrates. Thus, oral rolapitant is an effective and well tolerated NK1 RA that expands the treatment options for preventing delayed CINV in adults receiving HEC or MEC.<br />
DOI: 10.1007/s40265-017-0816-z PMID: 28929404 [Indexed for MEDLINE]<br />
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[4]. Drug Des Devel Ther. 2017 Sep 5;11:2621-2629. doi: 10.2147/DDDT.S133943. eCollection 2017.<br />
Recent developments in the clinical pharmacology of rolapitant: subanalyses in specific populations.<br />
Rapoport BL(1), Aapro M(2), Chasen MR(3), Jordan K(4), Navari RM(5), Schnadig I(6), Schwartzberg L(7).<br />
Author information: (1)The Medical Oncology Centre of Rosebank, Johannesburg, South Africa. (2)Breast Center, Genolier Cancer Center, Genolier, Switzerland. (3)Palliative Care, William Osler Health Services, Brampton, ON, Canada. (4)Department of Medicine V, University of Heidelberg, Heidelberg, Germany. (5)Division of Hematology Oncology, University of Alabama School of Medicine, Birmingham, AL, USA. (6)Compass Oncology, US Oncology Research, Tualatin, OR, USA. (7)West Clinic, Memphis, TN, USA.<br />
Knowledge of the involvement of the neurokinin substance P in emesis has led to the development of the neurokinin-1 receptor antagonists (NK-1 RAs) for control of chemotherapy-induced nausea and vomiting (CINV), in combination with serotonin type 3 receptor antagonists and corticosteroids. The NK-1 RA rolapitant, recently approved in oral formulation, has nanomolar affinity for the NK-1 receptor, as do the other commercially available NK-1 RAs, aprepitant and netupitant. Rolapitant is rapidly absorbed and has a long half-life in comparison to aprepitant and netupitant. All three NK-1 RAs undergo metabolism by cytochrome P450 (CYP) 3A4, necessitating caution with the concomitant use of CYP3A4 inhibitors, but in contrast to aprepitant and netupitant, rolapitant does not inhibit or induce CYP3A4. However, rolapitant is a moderate inhibitor of CYP2D6, and concomitant use with CYP2D6 substrates with narrow therapeutic indices should be avoided. Aprepitant, netupitant, and rolapitant have all demonstrated efficacy in the control of delayed CINV in patients receiving moderately and highly emetogenic chemotherapy in randomized controlled trials, including over multiple cycles of chemotherapy. We reviewed recent post hoc analyses of clinical trial data demonstrating that rolapitant is efficacious in the control of CINV in patient populations with specific tumor types, namely, breast cancers, gastrointestinal/colorectal cancers, and lung cancers. In addition, we show that rolapitant has efficacy in the control of CINV in specific age groups of patients receiving chemotherapy (<65 and ≥65 years of age). Overall, the safety profile of rolapitant in these specific patient populations was consistent with that observed in primary analyses of phase 3 trials.<br />
DOI: 10.2147/DDDT.S133943 PMCID: PMC5592904 PMID: 28919712 [Indexed for MEDLINE]<br />
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[5]. Rev Recent Clin Trials. 2017;12(3):193-201. doi: 10.2174/1574887112666170406104854.<br />
Rolapitant: An NK-1 Receptor Antagonist for the Prevention of Chemotherapy- Induced Nausea and Vomiting.<br />
Rapoport BL(1).<br />
Author information: (1)The Medical Oncology Centre of Rosebank, 129 Oxford Road, Corner Northwold, Saxonwold, Johannesburg, 2196. South Africa.<br />
BACKGROUND: Nausea and vomiting are among the most feared side effects of chemotherapy and can prevent cancer patients from completing their treatment regimens. Rolapitant is a highly selective neurokinin-1 (NK-1) receptor antagonist with very good oral activity, central nervous system penetration and a long (180-hour) plasma half-life. Unlike other available NK-1 receptor antagonists, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4. METHODS: Findings from recent phase II and III clinical trials of rolapitant in patients receiving highly or moderately emetogenic chemotherapy are reviewed and discussed. RESULTS: The addition of a single-dose of rolapitant to combination 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone regimens provided increased protection against chemotherapyinduced nausea and vomiting, a benefit that encompassed the entire at-risk period investigated (0-120 hours after initiation of chemotherapy) in patients receiving highly or moderately emetogenic chemotherapy. Rolapitant was well tolerated by patients in these trials, with the overall frequency of treatment- related adverse events similar in patients receiving rolapitant (7.0%) and active placebo (6.3%). CONCLUSION: Rolapitant's favorable toxicity profile and lack of CYP3A4-related drug-drug interactions indicate that it would be a suitable treatment for older patients or those with multiple comorbidities, who are likely to be receiving a number of concomitant medications. Future studies should focus on the role of rolapitant in the control of chemotherapy-induced nausea and vomiting in patients receiving multiple-day chemotherapy, specific chemotherapy agents or high-dose chemotherapy and stem cell support.<br />
DOI: 10.2174/1574887112666170406104854 PMID: 28393710 [Indexed for MEDLINE]
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