Rolapitant

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Rolapitant
Rolapitant (Patent Verified).svg
Names
Pronunciation/rˈlæpɪtænt/ roh-LAP-i-tant
Trade namesVarubi (US), Varuby (EU)
Other namesSCH 619734
  • (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]
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
US NLMRolapitant
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)
  • FC(F)(F)c(c4)cc(C(F)(F)F)cc4C(C)OCC3(c2ccccc2)NCC1(CC3)NC(=O)CC1
  • 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approved for medical use in the United States in 2015.[4] It was approved in Europe in 2017 but that approval was later withdrawn.[5] In the United States it costs about 670 USD per dose.[6]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

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. 1.0 1.1 1.2 1.3 1.4 "Varuby" (PDF). Retrieved 18 October 2021.
  2. 2.0 2.1 2.2 2.3 2.4 2.5 "Rolapitant Monograph for Professionals". Drugs.com. Retrieved 18 October 2021.
  3. 3.0 3.1 3.2 3.3 3.4 "Varubi- rolapitant tablet". DailyMed. 6 August 2019. Retrieved 21 August 2020.
  4. "DailyMed - VARUBI- rolapitant tablet". dailymed.nlm.nih.gov. Retrieved 18 October 2021.
  5. "Varuby". Retrieved 18 October 2021.
  6. 6.0 6.1 "Varubi Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 18 October 2021.
  7. 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 "Varuby: EPAR – Product Information" (PDF). European Medicines Agency. 2017-05-31.
  8. 8.0 8.1 "Varuby: EPAR – Public assessment report" (PDF). European Medicines Agency. 2017-05-31.
  9. BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 454. ISBN 978-0-85711-369-6.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. Retrieved 5 October 2016.

External links

External sites:
Identifiers: