Rolapitant- New drug to treat chemotherapy induced Nausea & Vomitting

September 2, 2015

Rolapitant is a substance P/neurokinin 1 (NK1) receptor antagonist indicated for use in combination with other antiemetic agents for the prevention of delayed nausea and vomiting associated with emetogenic chemotherapy.

The U.S. Food and Drug Administration approved Varubi (rolapitant) to prevent delayed phase chemotherapy-induced nausea and vomiting (emesis). Varubi is approved in adults in combination with other drugs (antiemetic agents) that prevent nausea and vomiting associated with initial and repeat courses of vomit-inducing (emetogenic and highly emetogenic) cancer chemotherapy.

NK-1 receptors are highly concentrated in the brain and bind neurokinin substance P. Activation of NK-1 receptors plays a central role in nausea and vomiting induced by emetogenic stimuli, including certain cancer chemotherapies.

A Positron Emission Tomography (PET) study with rolapitant in normal, healthy volunteers demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK-1 receptors at high levels for up to 120 hours.

VARUBI has a half-life of approximately 7 days, which may contribute to the ability of a single dose of VARUBI to cover the entire delayed CINV Phase (25-120 hours).

DESCRIPTION

VARUBI tablets contain 90 mg rolapitant (equivalent to 100 mg rolapitant hydrochloride), a substance P/neurokinin 1 (NK1) receptor antagonist. Rolapitant hydrochloride is chemically described as (5S,8S)-8- { [(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]methyl]}-8-phenyl­ 1,7-diazaspiro[4.5]decan-2-one monohydrochloride monohydrate. Its empirical formula is C25H26F6N2O2. HCl.H2O and its structural formula is:

rola

CLINICAL PHARMACOLOGY

Mechanism of Action

Rolapitant is a selective and competitive antagonist of human substance P/NK1 receptors.

Rolapitant does not have significant affinity for the NK2 or NK3 receptors or for a battery of other receptors, transporters, enzymes and ion channels.

Rolapitant is also active in animal models of chemotherapy-induced emesis.

Pharmacodynamics

NK1 Receptor Occupancy

A human Positron Emission Tomography (PET) study with rolapitant demonstrated that rolapitant crosses the blood brain barrier and occupies brain NK1 receptors. A dose-dependent increase in mean NK1 receptor occupancy was observed in the dose range from 4.5 mg to 180 mg of rolapitant. At the 180 mg dose of rolapitant, the mean NK1 receptor occupancy was 73% in the striatum at 120 hours after a single dose administration in healthy subjects. The relationship between NK1 receptor occupancy and the clinical efficacy of rolapitant has not been established.

Cardiac Electrophysiology

In a thorough QT study, rolapitant at doses up to four times higher than the recommended dose had no significant effects on the QT intervals.

INDICATIONS AND USAGE

VARUBI™ is a substance P/neurokinin 1 (NK1) receptor antagonist indicated in combination with other antiemetic 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.

DOSAGE AND ADMINISTRATION

• The recommended dosage is 180 mg rolapitant administered approximately 1 to 2 hours prior to the start of chemotherapy

• Administer in combination with dexamethasone and a 5-HT3 receptor antagonist, see full prescribing information for dosing information

• No dosage adjustment for dexamethasone is required.

CONTRAINDICATIONS

Concurrent use with thioridazine, a CYP2D6 substrate

ADVERSE REACTIONS

Most common adverse reactions (≥ 5%) are:

• Cisplatin Based Highly Emetogenic Chemotherapy: neutropenia and hiccups

• Moderately Emetogenic Chemotherapy and Combinations of Anthracycline and Cyclophosphamide: decreased appetite, neutropenia and dizziness

Safety & Efficacy

The safety and efficacy of Varubi were established in three randomized, double-blind, controlled clinical trials where Varubi in combination with granisetron and dexamethasone was compared with a control therapy (placebo, granisetron and dexamethasone) in 2,800 patients receiving a chemotherapy regimen that included highly emetogenic (such as cisplatin and the combination of anthracycline and cyclophosphamide) and moderately emetogenic chemotherapy drugs. Those patients treated with Varubi had a greater reduction in vomiting and use of rescue medication for nausea and vomiting during the delayed phase compared to those receiving the control therapy.

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