APREPITANT

Dr.RENJU.S.RAVI

OVERVIEW

INTRODUCTION

PATHOGENESIS OF EMESIS

SUBSTANCE-P

APREPITANT – MOA

- PK/PD

- USES

- ADR

- C/I

- INTERACTIONS

Other NK1 Receptor antagonists

INTRODUCTION

Aprepitant is a neurokinin 1(NK1) receptor antagonist approved by FDA in 2003 for the prevention of acute and delayed chemotherapy-induced nausea and vomiting (CINV).

PATHOGENESIS OF EMESIS

Cause

Emesis is a defense mechanism controlled by the area postrema of the medulla oblongata. There are various sources of input to the vomiting center.

Receptors on the floor of the fourth ventricle of the brain represent the chemoreceptor trigger zone.

The chemoreceptor trigger zone contains dopamine D2 receptors, 5-HT3 receptors, opioid receptors, acetylcholine receptors, and receptors for substance P.

Stimulation of different receptors are involved in different pathways leading to emesis. In the final common pathway, substance P, which activates the NK-1 receptor, appears to be involved.

Additionally, the vagal and enteric nervous system inputs transmit information regarding the state of the gastrointestinal system. Irritation of the GI mucosa by chemotherapy, radiation, distention, or acute infectious gastroenteritis activates the 5-HT3 receptors of these inputs.

Cytotoxic agents cause a detectable increase in blood levels of serotonin and its major metabolite, 5-Hydroxyindoleacetic acid (5-HIAA).

The presence of these chemicals in the blood activate 5-HT3 receptors in the chemoreceptor trigger zone, in turn releasing substance P, which activates NK1 receptors to cause an emetic response.

SUBSTANCE P

Substance P belongs to the tachykinin family of peptides.

Substance P is present in the central nervous system, where it is a neurotransmitter and in the GIT, where it may play a role as a transmitter in the enteric nervous system and as a local hormone.

Substance P - behavior, anxiety, depression, nausea, and emesis.

It is a potent arteriolar vasodilator, mediated by release of nitric oxide from the endothelium.

Also known to stimulate cell growth in culture.

The actions are mediated by three G protein-coupled tachykinin receptors designated NK1, NK2, and NK3

Substance P is the preferred ligand for the NK1 receptor, the predominant tachykinin receptor in the human brain.

NK1 is a G protein-coupled receptor located in the central and peripheral nervous system.

It is found in high concentrations in the vomiting center of the brain

also plays a key part in the transmission of pain impulses from the peripheral receptors to CNS

EMETOGENIC POTENTIAL OF ANTICANCER DRUGS

APREPITANT

Aprepitant is a highly selective NK1 antagonist approved by US-FDA in march 2003 for the treatment of chemotherapy induced nausea and vomiting.

ACTIONS

inhibit both the acute and delayed emesis induced by cytotoxic drugs by blocking Substance P in the brain's neurons.

selectively antagonize NK1 receptors, while having very low affinity to other common receptors such as serotonin, dopamine, and corticosteroids.

It has also been shown to increase the efficacy of the 5HT3 receptor antagonists and corticosteroids.

Pharmacokinetics

Orally active

Bioavailability of 60 - 65% ; unaffected by food

Half life 9-13hrs

95% bound to plasma proteins

Metabolism in Liver (CYP3A4)

Excreted in urine(50%) and in faeces(50%)

USES

- Chemotherapy induced nausea and vomiting (CINV)

- Post operative nausea and vomiting (PONV)

- Cyclic vomiting syndrome

DOSE

CINV - 125 mg on day1 (before chemotherapy) and then 80mg on days 2 and 3 (after chemotherapy)

PONV – 40mg within 3hrs prior to induction

Should be given with a 5HT3 antagonist and Dexamethasone

Dose of dexamethasone should be reduced by 50%

Adverse Effects Fatigue

Hiccups

Heartburn

Diarrhoea

Dizziness

Elevation of Liver Enzymes

Cases of angioedema, urticaria, SJS

C/I – Patients on cisapride/pimozide- QT prolongation

INTERACTIONS

Aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19.

As a moderate inhibitor of CYP3A4, aprepitant may inhibit the metabolism of other drugs metabolized by the CYP3A4 pathway.

Drugs that inhibit CYP3A4 metabolism increase aprepitantplasma levels.

Aprepitant decreases INR in patients taking warfarin.

Specific interaction has been demonstrated with oxycodone, where aprepitant both increased the efficacy and worsened the side effects of oxycodone.

Other NK1 Receptor Antagonists…

Fosaprepitant – prodrug ; I/V infusion

Casopitant – Phase 3 trial for CINV

Vestipitant – antiemetic /anxiolytic under trial for tinnitus and insomnia

Maropitant – under trial for motion sickness and vomiting

SUMMARY

Aprepitant – a clear cut therapeutic advance

Good Safety profile

Effective in Breast cancer patients

(cyclophosphamide/anthracycline based chemotherapy)

Potential for drug interactions

High cost of the drug