Rolapitant

Rolapitant (INN,^[2] 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).^[3] 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.^[4][5][6][7]

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
Routes of administration	By mouth (tablets), intravenous
Drug class	NK1 receptor antagonists, antiemetics
ATC code	A04AD14 (WHO)
Legal status
Legal status	US: ℞-only[1] 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%)[1]
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
CompTox Dashboard (EPA)	DTXSID90203740
ECHA InfoCard	100.243.022
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

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.^[1] The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT₃ antagonist.^[8]

Contraindications

Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant.^[1] Under the European approval, it is contraindicated in combination with St. John's Wort, which is expected to accelerate inactivation of rolapitant.^[8]

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%).^[1]

Overdose

Up to eightfold therapeutic doses have been given in studies without problems.^[8]

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%.^[8]

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.^[8]

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.^[9]

Pharmacokinetics

The major active metabolite, M19 (C4-pyrrolidine-hydroxylated rolapitant).^[8] 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.^[8]

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.^[8]

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.^[9]