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Zavegepant

Zavegepant_for_migraine Zavegepant_for_migraine
Zavegepant_for_migraine Zavegepant_for_migraine

Zavegepant is the first calcitonin gene-related peptide (CGRP) receptor antagonist that can be administered intranasally for migraine management.

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Introduction

Zavegepant is the first calcitonin gene-related peptide (CGRP) receptor antagonist that can be administered intranasally for migraine management. It is a third-generation, high-affinity, selective, and structurally distinct small molecule that is highly soluble, thus making it a potential candidate for  inhalational, nasal, subcutaneous, and oral routes of delivery. [1]

The FDA authorized Zavegepant nasal spray use in March 2023 for acute migraine treatment without or with aura in adults.

Pharmacological Class: CGRP receptor antagonist

Indications

In adults, Zavegepant is recommended for acute management of migraine with or without aura. It is not advised for migraine prophylaxis.

Pharmachologic action

Although the pathophysiology of migraine has not yet been fully determined, some vasoactive chemicals and neurotransmitters including substance P, nitric oxide, neurokinin A, and CGRP may play a role in the processes behind the neurovascular and cortical spreading of depression.

In acute migraine, the CGRP release controls neuronal excitability and boosts vasodilation, facilitating pain responses in migraine pain transmission systems like the trigeminal system. In order to suppress vasodilation processes from occurring, CGRP receptor antagonists like Zavegepant desensitize neuronal circuits. [2]

Dosage

  • Zavegepant's maximum dosage is 10 mg (one spray) per 24 hours.
  • A single spray of 10 mg Zavegepant should be administered in one nostril, as required.
  • It has not been shown safe to relieve more than eight migraines in 30 days. [3] 

Pharmacokinetics

Absorption

The maximal plasma concentration was detected about 30 minutes after a single intranasal administration of 10 mg Zavegepant. Zavegepant's absolute bioavailability administered with a nasal spray is about 5%. A single intranasal dosage of Zavegepant exhibits a dose-proportional pharmacokinetics of up to 40 mg (4 times the advised dose of 10 mg). With once-daily Zavegepant taken for 14 days, no sign of drug accumulation was reported.

People suffering from moderate hepatic impairment (Child-Pugh B) have Cmax and AUC values that are 16% and 1.9 fold higher respectively than those of healthy individuals. On the basis of the clinical safety data and the minimal cumulative drug exposures, it is not anticipated that these alterations will have a substantial impact. The changes in Zavegepant pharmacokinetics are not anticipated to have any clinically relevant effects in persons with estimated creatinine clearance of > 30 mL/min. People with a creatinine clearance of 15 to 29 mL/min may experience elevated Zavegepant exposure.

 

Volume of distribution

Around 1774 L is the mean apparent volume of distribution.

 

Protein binding

Zavegepant exhibits a plasma protein binding of about 90%.

 

Metabolism

Zavegepant is majorly metabolized in vitro by CYP3A4, whereas, CYP2D6 metabolizes Zavegepant to a lesser extent. Following a single intravenous administration of [14C]-Zavegepant (5 mg), 90% of the circulating dosage was unaltered Zavegepant. In plasma, none of the Zavegepant metabolites identified was discovered at a proportion greater than 10%.

 

Route of elimination

Zavegepant is mostly eliminated via the biliary/fecal route, with the renal pathway serving only a small part in its removal. About 11% and 80% of the dosage of 5 mg [14C]-Zavegepant administered via the intravenous route to healthy male participants were recovered as unmodified Zavegepant in urine and feces, respectively.

 

Half-life

Intranasal Zavegepant has an efficient half-life of 6.55 hours following a dose of 10 mg.
 

Clearance

Intranasal Zavegepant shows a mean apparent clearance of 266 L/h. [2]

Contraindications

It is contraindicated in:

  • Individuals who have previously experienced a hypersensitivity reaction to Zavegepant or any of its constituents
  • Patients with severe hepatic impairment
  • Patients with creatinine clearance < 30 mL/min [3]

Drug interaction

  • Do not combine Zavegepant with medications that block the Na+-taurocholate co-transporting polypeptide (NTCP) or organic anion transporting polypeptide 1B3 (OATP1B3) transporters as it may result in a significant rise in Zavegepant exposure.
  • NTCP or OATP1B3 transporter inducers should not be used together with Zavegepant as it may induce a reduction in Zavegepant exposure.
  • Intranasal decongestants should not be used with Zavegepant as they may minimize  Zavegepant's absorption; if cannot be avoided, they should be administered at least one hour after receiving Zavegepant. [3]

Side effects

Following are the most commonly reported side effects of Zavegepant:

  • Vomiting
  • Nasal discomfort
  • Nausea
  • Taste disorders [3]

Precautions

Hypersensitivity Reactions: Zavegepant can cause hypersensitivity responses such as urticaria and facial edema. Stop using Zavegepant if a severe hypersensitivity reaction occurs. [3]

Clinical evidence

Safety, efficacy, and tolerability of Zavegepant nasal spray to treat migraine

In a dose-ranging, randomized, placebo-controlled, phase 2/3 trial, Zavegepant nasal spray in single doses of 10 or 20 mg exhibited a good safety profile and was useful to relieve migraine. Out of 1673 volunteers (age 18 to 79 years) who were randomly allocated, 1588 received study medication; 1581 (mean age 40.8 years; 85.5% female) were evaluated for effectiveness. The enrolled participants received either placebo (n = 401) or doses of 5 mg (n = 387), 10 mg (n = 391), or 20 mg (n = 402) of Zavegepant.

Compared to placebo, Zavegepant 10 and 20 mg demonstrated superior efficacy on the coprimary outcomes of freedom from the most bothersome symptom at two hours postdose (placebo: 33.7% [98.3% CI, 28.0, 39.3];10 mg: 41.9% [98.3% CI, 36.0, 47.9]; 20 mg: 42.5% [98.3% CI, 36.6, 48.4]) and pain freedom at two hours postdose (placebo: 15.5% [98.3% confidence interval (CI), 11.1, 19.8]; 10 mg: 22.5% [98.3% CI, 17.5, 27.6]; 20 mg: 23.1% [98.3% CI, 18.1, 28.2]). For the 5 mg dosage, the results were insignificant. [4]

Zavegepant 10 mg nasal spray showed good safety and tolerability profiles while being effective in the acute management of migraine in a multicenter, placebo-controlled, randomized, double-blind, phase 3 trial. Adults (18 years of age or older) with a history of 2-8 severe or moderate migraine attacks per month were included in this trial. They were then randomly allocated (1:1) to receive either Zavegepant 10 mg nasal spray or a matching placebo and self-treated a single migraine attack with severe or moderate pain intensity.

Two hours following the treatment dose, more number of subjects in the Zavegepant group than in the placebo group had freedom from their most bothersome symptom (247 [40%]vs 201 [31%], risk difference 8·7 percentage points) and pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants, risk difference 8·8 percentage points). [5] A phase 2/3 trial investigating the long-term safety of Zavegepant 10 mg intranasal doses up to eight times per month, up to one year, is currently in progress. [1]

References

    1. Noor N, Angelette A, Lawson A, Patel A, Urits I, Viswanath O et al. A Comprehensive Review of Zavegepant as Abortive Treatment for Migraine. Health Psychology Research. 2022 Jun 28;10(3):35506.

    2. Zavegepant. Drug Bank. Accession Number DB15688. Available online from: https://go.drugbank.com/drugs/DB15688 [Last accessed on: 18 April 2023]

    3. Zavegepant. FDA LABEL. Available online from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/216386s000lbl.pdf

    [Last accessed on: 18 April 2023]

    4. Croop R, Madonia J, Stock DA, Thiry A, Forshaw M, Murphy A et al. Zavegepant nasal spray for the acute treatment of migraine: A Phase 2/3 double‐blind, randomized, placebo‐controlled, dose‐ranging trial. Headache: The Journal of Head and Face Pain. 2022 Oct;62(9):1153-63.

    5. Lipton RB, Croop R, Stock DA, Madonia J, Forshaw M, Lovegren M et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurology. 2023 Mar;22(3):209-217.

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