Rolapitant

Rolapitant
Names
Pronunciation/roʊˈlæpɪtænt/ roh-LAP-i-tant
Trade namesVarubi (US), Varuby (EU)
Other namesSCH 619734
IUPAC name
  • (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)- 8-phenyl-1,7-diazaspiro[4.5]decan-2-one
Clinical data
Drug classNK1 receptor antagonist[1]
Main usesChemotherapy-induced nausea and vomiting (CINV)[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • US: N (Not classified yet)
    Routes of
    use    		By mouth (tablets), intravenous
    Typical doseBy mouth: 180 mg[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa615041
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailabilitynearly 100%
    Protein binding99.8%
    MetabolismCYP3A4
    MetabolitesC4-pyrrolidine-hydroxylated rolapitant (major)
    Elimination half-life169–183 hours
    ExcretionFeces (52–89%), urine (9–20%)[3]
    Chemical and physical data
    FormulaC25H26F6N2O2
    Molar mass500.485 g·mol−1
    3D model (JSmol)
    SMILES
    • FC(F)(F)c(c4)cc(C(F)(F)F)cc4C(C)OCC3(c2ccccc2)NCC1(CC3)NC(=O)CC1
    InChI
    • InChI=1S/C25H26F6N2O2/c1-16(17-11-19(24(26,27)28)13-20(12-17)25(29,30)31)35-15-23(18-5-3-2-4-6-18)10-9-22(14-32-23)8-7-21(34)33-22/h2-6,11-13,16,32H,7-10,14-15H2,1H3,(H,33,34)/t16-,22-,23-/m1/s1
    • Key:FIVSJYGQAIEMOC-ZGNKEGEESA-N

    Rolapitant, sold under the brand name Varubi among others, is a medication used for chemotherapy-induced nausea and vomiting (CINV).[2] It is more commonly used for nausea that occurs more than 24 hours after chemotherapy.[1] It is used either by mouth or by injection into a vein.[2]

    Common side effects include hiccups, dizziness, headache, and tiredness.[2][1] It interacts with St. John's wort.[1] It works by blocking blocking NK1 receptor.[1]

    Rolapitant was approved for medical use in the United States in 2015.[4] It was approved in Europe in 2017 but that approval was later withdrawn.[5] In the United States it costs about 670 USD per dose.[6]

    Medical uses

    Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy.[3] The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT3 antagonist.[7]

    Dosage

    Often it is taken as a dose of 180 mg.[2]

    Contraindications

    Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant.[3] Under the European approval, it is contraindicated in combination with St. John's Wort, which is expected to accelerate inactivation of rolapitant.[7]

    Side effects

    In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT3 antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT3 antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%).[3]

    Overdose

    Up to eightfold therapeutic doses have been given in studies without problems.[7]

    Interactions

    Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphan have increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.[7]

    Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations.[7]

    Pharmacology

    Further information: Aprepitant § Mechanism of action

    Pharmacodynamics

    Both rolapitant and its active metabolite M19 block the NK1 receptor with high affinity and selectivity: to block the closely related receptor NK2 or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary.[8]

    Pharmacokinetics

    The major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant).[7] The stereochemistry of the hydroxyl group is unknown.

    Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins.[7]

    It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites. Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range.[7]

    Chemistry

    The drug is used in form of rolapitant hydrochloride monohydrate, a white to off-white, slightly hygroscopic crystalline powder. Its maximum solubility in aqueous solutions is at pH 2–4.[8]

    Society and culture

    Cost

    In the United States it costs about 670 USD per dose.[6] In Wales it was deemed to be of unclear cost effectiveness and was thus not recommended for use.[9]

    Names

    Rolapitant is the INN.[10]

    See also

    References

    1. 1 2 3 4 5 "Varuby" (PDF). Archived (PDF) from the original on 8 May 2020. Retrieved 18 October 2021.
    2. 1 2 3 4 5 6 "Rolapitant Monograph for Professionals". Drugs.com. Retrieved 18 October 2021.
    3. 1 2 3 4 5 "Varubi- rolapitant tablet". DailyMed. 6 August 2019. Archived from the original on 26 October 2020. Retrieved 21 August 2020.
    4. ↑ "DailyMed - VARUBI- rolapitant tablet". dailymed.nlm.nih.gov. Archived from the original on 26 October 2020. Retrieved 18 October 2021.
    5. ↑ "Varuby". Archived from the original on 26 June 2021. Retrieved 18 October 2021.
    6. 1 2 "Varubi Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 18 October 2021.
    7. 1 2 3 4 5 6 7 8 "Varuby: EPAR – Product Information" (PDF). European Medicines Agency. 2017-05-31. Archived (PDF) from the original on 2018-03-18. Retrieved 2021-08-04.
    8. 1 2 "Varuby: EPAR – Public assessment report" (PDF). European Medicines Agency. 2017-05-31. Archived (PDF) from the original on 2018-03-18. Retrieved 2021-08-04.
    9. ↑ BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 454. ISBN 978-0-85711-369-6.{{cite book}}: CS1 maint: date format (link)
    10. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN). Recommended International Nonproprietary Names (Rec. INN): List 59" (PDF). World Health Organization. p. 64. Archived (PDF) from the original on 18 May 2016. Retrieved 5 October 2016.
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