AKYNZEO CAPSULE 300MG/0.5MG

Netupitant
Palonosetron

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

2-[3,5-Bis(trifluoromethyl)phenyl]-N,2-dimethyl-N-[4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3-pyridinyl]propanamide | Netupitant |

Description

Netupitant is an antiemitic drug approved by the FDA in October 2014 for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy. Netupitant is a neurokinin 1 receptor antagonist. The combination drug is marketed by Eisai Inc. and Helsinn Therapeutics (U.S.) Inc. under the brand Akynzeo®.

Indication

Netupitant is an antiemitic drug approved by the FDA in October 2014 for use in combination with palonosetron for the prevention of acute and delayed vomiting and nausea associated with cancer chemotherapy including highly emetogenic chemotherapy.

Mechanism of Action

Delayed emesis (vomiting) has been largely associated with the activation of tachykinin family neurokinin 1 (NK1) receptors (broadly distributed in the central and peripheral nervous systems) by substance P. As shown in in vitro and in vivo studies, netupitant inhibits substance P mediated responses.

Pharmacodynamics

Not Available

Pharmacokinetics

Absorption:

Upon oral administration of a single dose of netupitant, netupitant started to be measurable in plasma between 15 minutes and 3 hours after dosing. Plasma concentrations reached Cmax in approximately 5 hours. There was a greater than dose-proportional increase in the systemic exposure with the dose increase from 10 mg to 300 mg and a dose-proportional increase in systemic exposure with a dose increase from 300 mg to 450 mg.

Distribution:

In cancer patients, Vz/F: 1982 ± 906 L (mean ± SD).

Metabolism:

Once absorbed, netupitant is extensively metabolized to form three major metabolites: desmethyl derivative, M1; N-oxide derivative, M2; and OH-methyl derivative, M3. Metabolism is mediated primarily by CYP3A4 and to a lesser extent by CYP2C9 and CYP2D6. Metabolites M1, M2 and M3 were shown to bind to the substance P/neurokinin 1 (NK1) receptor.

Elimination:

Primarily fecal.

Half-life

96 hours with CV% of 61.

Clearance

estimated systemic clearance of 20.3 ± 9.2 L/h (mean ± SD).

Toxicity

Daily oral administration of netupitant in rats at doses up to 30 mg/kg (1.9 times the human AUC in male rats and 3.7 times the human AUC in female rats at the recommended human dose) had no effects on fertility or reproductive performance.

Source of information: Drugbank (External Link). Last updated on: 3rd July 18
*Trade Name used in the content below may not be the same as the HSA-registered product.

Active Ingredient / Synonyms

(3aS)-2-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-2,3,3a, 4,5,6-hexahydro-1H-benz[de]isoquinolin-1-one | (3aS)-2,3,3a,4,5,6-hexahydro-2-[(3S)-3-quinuclidinyl]-1H-benz[de]isoquinolin-1-one | Palonosetron | Palonosétron | Palonosetrón | Palonosetronum | Palonosetron |

Description

Palonosetron (INN, trade name Aloxi) is a 5-HT3 antagonist used in the prevention and treatment of chemotherapy-induced nausea and vomiting (CINV). It is the most effective of the 5-HT3 antagonists in controlling delayed CINV nausea and vomiting that appear more than 24 hours after the first dose of a course of chemotherapy and is the only drug of its class approved for this use by the U.S. Food and Drug Administration. As of 2008, it is the most recent 5-HT3 antagonist to enter clinical use.

Indication

For the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy, as well as prevention of acute nausea and vomiting associated with highly emetogenic cancer chemotherapy. Also used for the prevention of postoperative nausea and vomiting for up to 24 hours post operation.

Mechanism of Action

Palonosetron is a selective serotonin 5-HT3 receptor antagonist. The antiemetic activity of the drug is brought about through the inhibition of 5-HT3 receptors present both centrally (medullary chemoreceptor zone) and peripherally (GI tract). This inhibition of 5-HT3 receptors in turn inhibits the visceral afferent stimulation of the vomiting center, likely indirectly at the level of the area postrema, as well as through direct inhibition of serotonin activity within the area postrema and the chemoreceptor trigger zone. Alternative mechanisms appear to be primarily responsible for delayed nausea and vomiting induced by emetogenic chemotherapy, since similar temporal relationships between between serotonin and emesis beyond the first day after a dose have not been established, and 5-HT3 receptor antagonists generally have not appeared to be effective alone in preventing or ameliorating delayed effects. It has been hypothesized that palonosetron's potency and long plasma half-life may contribute to its observed efficacy in preventing delayed nausea and vomiting caused by moderately emetogenic cancer chemotherapy.

Pharmacodynamics

Palonosetron is an antinauseant and antiemetic agent indicated for the prevention of nausea and vomiting associated with moderately-emetogenic cancer chemotherapy and for the prevention of postoperative nausea and vomiting. Palonosetron is a highly specific and selective serotonin 5-HT3 receptor antagonist that is pharmacologically related to other 5-HT3 receptor antagonists, but differs structurally. Palonosetron has a high affinity for 5-HT3 receptors, but has little to no affinity for other receptors. The serontonin 5-HT3 receptors are located on the nerve terminals of the vagus in the periphery, and centrally in the chemoreceptor trigger zone of the area postrema. It is suggested that chemotherapeutic agents release serotonin from the enterochromaffin cells of the small intestine by causing degenerative changes in the GI tract. The serotonin then stimulates the vagal and splanchnic nerve receptors that project to the medullary vomiting center, as well as the 5-HT3 receptors in the area postrema, thus initiating the vomiting reflex, causing nausea and vomiting.

Pharmacokinetics

Absorption:

Low oral bioavailability.

Distribution:

* 8.3 ± 2.5 L/kg

Metabolism:

Hepatic (50%), primarily CYP2D6-mediated, although CYP3A4 and CYP1A2 are also involved.

Elimination:

After a single intravenous dose of 10 mcg/kg [14C]-palonosetron, approximately 80% of the dose was recovered within 144 hours in the urine

Half-life

Approximately 40 hours

Clearance

* 160 +/- 35 mL/h/kg

Toxicity

A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

References

  1. Health Science Authority of Singapore - Reclassified POM
  2. Drugbank

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Approval Information

AKYNZEO CAPSULE 300MG/0.5MG was registered with Health Science Authority of Singapore by MUNDIPHARMA PHARMACEUTICALS PTE LTD. It is marketed with the registration number of SIN15031P with effective from 2016-06-08.

This product contains 300mg of Netupitant, and 0.5mg of Palonosetron in the form of CAPSULE, GELATIN-COATED.

The medicine was manufactured by Helsinn Birex Pharmaceuticals Ltd. in IRELAND, and Catalent Pharma Solutions LLC in UNITED STATES

It is a Presciption Only Medicine which can only be obtained from a doctor or a dentist, or from a pharmacist with a prescription from a Singapore-registered doctor or dentist.

Anatomical Therapeutic Chemical (ATC) Classification

ATC Code: A04AA55

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