Chemistry:Rolapitant

Short description: Pharmaceutical drug

Rolapitant

Clinical data
Pronunciation	/roʊˈlæpɪtænt/ roh-LAP-i-tant
Trade names	Varubi (US), Varuby (EU)
Other names	SCH 619734
AHFS/Drugs.com	Monograph
MedlinePlus	a615041
License data	EU EMA: by INN US DailyMed: Rolapitant
Pregnancy category	US: N (Not classified yet)
Routes of administration	By mouth (tablets), intravenous
Drug class	NK1 receptor antagonists, antiemetics
ATC code	A04AD14 (WHO)
Legal status
Legal status	US: ℞-only EU: Rx-only
Pharmacokinetic data
Bioavailability	nearly 100%
Protein binding	99.8%
Metabolism	CYP3A4
Metabolites	C4-pyrrolidine-hydroxylated rolapitant (major)
Elimination half-life	169–183 hours
Excretion	Feces (52–89%), urine (9–20%)
Identifiers
IUPAC name (5S,8S)-8-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}methyl)- 8-phenyl-1,7-diazaspiro[4.5]decan-2-one
CAS Number	552292-08-7 Y
PubChem CID	10311306
IUPHAR/BPS	5749
DrugBank	DB09291 Y
ChemSpider	8486772
UNII	NLE429IZUC
KEGG	D10742 as HCl: D08988
ChEBI	CHEBI:90908 Y
Chemical and physical data
Formula	C25H26F6N2O2
Molar mass	500.485 g·mol−1
3D model (JSmol)	Interactive image
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 (INN, trade name Varubi /vəˈruːbi/ və-ROO-bee in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK₁ receptor antagonist (antagonist for the NK₁ receptor). It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application.

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. The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT₃ antagonist.

Contraindications

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

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%).

Overdose

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

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%.

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.

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.

Pharmacokinetics

The major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant). 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.

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.

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.

See also

• Palonosetron

External links

• "Rolapitant". Drug Information Portal. U.S. National Library of Medicine. https://druginfo.nlm.nih.gov/drugportal/name/rolapitant. 
• "Rolapitant Injection: MedlinePlus Drug Information". 20 August 2020. https://medlineplus.gov/druginfo/meds/a618019.html.