Identification

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Name
Vayarin
Accession Number
DB09328
Type
Biotech
Groups
Approved, Investigational
Description

Vayarin is a prescription medical food for the clinical dietary management of certain lipid imbalances blamed to be associated with attention deficit hyperactivity disorder (ADHD) in children. Vayarin contains Lipirinen, a proprietary composition containing phosphatidylserine-omega 3, EPA (eicosapentaenoic acid), and docosahexaenoic acid (DHA) 5,13. Vayarin is currently available only by prescription in the USA 7. This drug has also been used for management of hypertriglyceridemia 8.

Vayarin is an orally administered prescription medical food for the clinical dietary management of complex lipid imbalances thought to be associated with ADHD. Vayarin is a specially formulated and designed to address the distinct, previously determined lipid nutritional requirements of children with ADHD, the dietary management of which cannot be achieved with lifestyle modification 7.

Vayarin is a novel therapy for ADHD that appears to be effective in several studies 6,7,8. Approximately 60% of the users who completed 12 weeks of therapy reported subjective benefits from treatment. A slow response time of 12 weeks is an impediment to successful management of ADHD as only 41.6% of subjects prescribed Vayarin remained compliant for the duration of the study. Cost of the drug and patient aversion to the taste of Vayarin were significant reasons for therapy failure 7.

Synonyms
  • Phosphatidylserine, DHA, and EPA
Categories
UNII
Not Available
CAS number
Not Available

Pharmacology

Indication

ADHD in children, hypertriglyceridemia 7,8.

Pharmacodynamics

Compared to healthy children of the same age, children with ADHD have lower circulating concentrations of omega-3 long-chain polyunsaturated fatty acid. These lipids, found in the brain, play an essential role in central nervous system development and function. It has been reported that omega-3 fatty acid deficiency is directly associated with decreased brain phosphatidylserine, which is mainly in the form of phosphatidylserine-Omega-3 (Ps-Omega-3) 5,7.

PS-Omega-3 such as Vayarin, are believed to be essential in the functioning of neuronal cell membranes, in activities such as signal transduction, secretory vesicle release, cell-to-cell communication, and cell growth regulation. Reduced levels of PS-Omega-3 and omega-3 fatty acids may play an important role in the pathogenesis of ADHD and other neuronal disorders. Vayarin is a proprietary lipid composition of phosphatidylserine-Omega-3 (PS-Omega-3), enriched with eicosapentaenoic acid. This formula has been designed to provide the essential lipids to brain tissues in order to support and maintain proper brain function. Additionally, the enrichment of EPA in the Vayarin medical food allows for better regulation of lipids and acts on the specific imbalances that are thought to be associated with ADHD 1,5.

Current studies are underway for the efficacy of Vayarin in ADHD and autism spectrum disorder co-morbidity 5. In addition, studies of Vayarin in adults using MRI to study alterations in radiographic findings are currently underway, allowing for other possible benefits of this medication 6.

Mechanism of action

Phosphatidylserine (PS) in the mammalian nervous system, containing high levels of omega-3 fatty acids, has been implicated in numerous membrane-associated functions, such as maintaining the integrity of cell membranes, cell excitability and cell-to-cell recognition and communication. While the exact mechanism by which this medical food exerts its effects is not fully understood, PS has been found to regulate important proteins in neuronal cell membranes, including sodium/calcium ATPase and protein kinase C, which perform crucial functions in many signal transduction pathways. Similarly, PS interacts with Raf-1 protein kinase 10 to promote a cascade of reactions that are believed to be involved in the survival of cells 10. Additionally, PS has been found to influence neurotransmitter activity, such as the release of acetylcholine (Ach), dopamine, and noradrenaline. In addition, it is also thought to increase brain glucose concentrations 10. Administration of specially processed formulations consisting of PS conjugated to omega-3 fatty acids was found to significantly increase DHA levels in the brain tissue of rats 10.

Absorption

Phosphatidylserine (the main component of this medical food) is an endogenous substance found in the human body. This medication is metabolized mainly in the intestines by decarboxylases in the mucosal cells 10. The bioavailability of the ingested PS is poorly demonstrated to extensive metabolism in the intestine before absorption, and due to the fact that PS is transported and rapidly converted into other endogenous constituents 11.

In one study, after oral administration of Vayarin to rats, most of the isotope label recovered from blood samples remained as the parent compound, PS, for up to 60 min after administration. After 24 h, metabolites were recovered from the blood, primarily as lysophosphatidylethanolamine and lysophosphatidylcholine. When radiolabeled PS was administered (orally or intraperitoneally) in animals, the radioactivity found in the urine was primarily metabolized (water soluble), whereas the 60-65% of fecal radioactivity was mainly associated with lipids. The major metabolite recovered in the feces was lysoPS after oral administration 11.

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Phospholipids can break down into various substrates or remain intact and absorbed in the circulatory system and cross the blood brain barrier. Following dietary ingestion of PS, fatty acids esterified to the PS molecule are hydrolyzed by pancreatic enzymes, forming lyso-PS and free fatty acids (FFA). After the lyso-PS is absorbed by the intestinal mucosa, it can be re-acylated into PS, while partially converted into other phospholipids. Phosphatidylserine and other phospholipids formed inside the enterocytes can either be transported in the lymphatic circulation as chylomicrons or in the hepatic circulation, and enter the systemic circulation for distribution across the body. Current evidence shows that ingested phosphatidylserine reaches the systemic circulation and is incorporated into the phospholipids pool as phosphatidylethanolamine and other metabolites 10,13.

The omega-3 polyunsaturated fatty acid metabolism cycle begins with a series of desaturation, elongation and β-oxidation reactions. In a study of healthy volunteers and patients with hypertriglyceridemia, eicosapentaenoic acid, and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters (Vayarin) induced significant, dose-dependent increases in serum phospholipid eicosapentaenoic acid content, though increases in DHA content were less significant and not dose-dependent when administered as ethyl esters. Uptake of EPA and DHA into serum phospholipids in subjects treated with Vayarin was independent of age (<49 years versus ≥49 years). Females were found to have more uptake of EPA into serum phospholipids than males 8.

The effect of a mixture of free fatty acids (FFA), EPA/DHA and their FFA-albumin conjugate on cytochrome P450-dependent monooxygenase activities was assessed in human liver microsomes. At the 23 μM concentration, FFA resulted in a less than 32% inhibition of CYP1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A. At the 23 μM concentration, the FFA-albumin conjugate resulted in a less than 20% inhibition of CYP2A6, 2C19, 2D6, and 3A, with a 68% inhibition being seen for CYP2E1 8.

In healthy volunteers and in patients with hypertriglyceridemia (HTG), EPA and DHA were absorbed when administered as ethyl esters orally. Omega-3-acids administered as ethyl esters (Vayarin) induced significant, dose–dependent increases in serum phospholipid EPA content, though increases in DHA content were less marked and not dose-dependent when administered as ethyl esters. Uptake of EPA and DHA into serum phospholipids in subjects treated with Vayarin was independent of age (<49 years vs. ≥49 years). Females tended to have more uptake of EPA into serum phospholipids than males. Pharmacokinetic data on Vayarin in children are not available 10,12.

Route of elimination

For all routes of administration, about 60% of the ingested PS is excreted in feces, while 10% is eliminated in the urine 10.

Half life

About 2h 11

Clearance

Mainly in the feces and urine 10.

Toxicity

The safety phosphatidyl serine conjugated to omega-3 (PS-Omega-3) is supported by several pre-clinical studies. Multiple dose safety studies in rats and dogs showed that oral administration of PS-Omega-3 at doses up to 1000 mg/kg/day for up to 6 months was without any significant effects. Teratogenicity studies in rats demonstrate that when given at doses up to 200 mg/kg/day and in rabbits at doses up to 450 mg/kg/ day, Ps Omega-3 (the main component of this medical food) did not affect embryonic and fetal development. The mutagenic potential of PS-Omega-3 was investigated in several cell types and revealed no significant findings. In a micronucleus test, PS-Omega-3 was given to mice at total dosages of 30, 150 and 300 mg/kg in two equal doses separated by 24 hours. The results of the study did not demonstrate any evidence of mutagenic properties or incidence of bone marrow toxicity 10.

In rats, Ld50 was greater than 5 mg/Kg for PS 10,12.

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcetaminophenVayarin may increase the hepatotoxic activities of Acetaminophen.
AnilineThe metabolism of Aniline can be decreased when combined with Vayarin.
Benzyl alcoholThe metabolism of Benzyl alcohol can be decreased when combined with Vayarin.
ChlorzoxazoneThe metabolism of Chlorzoxazone can be decreased when combined with Vayarin.
EnfluraneThe metabolism of Enflurane can be decreased when combined with Vayarin.
EthanolThe metabolism of Ethanol can be decreased when combined with Vayarin.
EthosuximideThe metabolism of Ethosuximide can be decreased when combined with Vayarin.
FelbamateThe metabolism of Felbamate can be decreased when combined with Vayarin.
HalothaneThe metabolism of Halothane can be decreased when combined with Vayarin.
IsofluraneThe metabolism of Isoflurane can be decreased when combined with Vayarin.
Additional Data Available
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    Extended Description

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  • Severity
    Severity

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  • Evidence Level
    Evidence Level

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  • Action
    Action

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Food Interactions
Not Available

References

General References
  1. Hamilton L, Greiner R, Salem N Jr, Kim HY: n-3 fatty acid deficiency decreases phosphatidylserine accumulation selectively in neuronal tissues. Lipids. 2000 Aug;35(8):863-9. [PubMed:10984109]
  2. Manor I, Magen A, Keidar D, Rosen S, Tasker H, Cohen T, Richter Y, Zaaroor-Regev D, Manor Y, Weizman A: Safety of phosphatidylserine containing omega3 fatty acids in ADHD children: a double-blind placebo-controlled trial followed by an open-label extension. Eur Psychiatry. 2013 Aug;28(6):386-91. doi: 10.1016/j.eurpsy.2012.11.001. Epub 2013 Jan 9. [PubMed:23312676]
  3. Mozzi R, Buratta S, Goracci G: Metabolism and functions of phosphatidylserine in mammalian brain. Neurochem Res. 2003 Feb;28(2):195-214. [PubMed:12608694]
  4. WISE EM Jr, ELWYN D: RATES OF REACTIONS INVOLVED IN PHOSPHATIDE SYNTHESIS IN LIVER AND SMALL INTESTINE OF INTACT RATS. J Biol Chem. 1965 Apr;240:1537-48. [PubMed:14285489]
  5. Efficacy Study of Vayarin in Children With Autism and Comorbid Attention Deficit Hyperactivity Disorder (ADHD) [Link]
  6. Neurobiological Basis of Response to Vayarin in Adults With ADHD: an fMRI Study of Brain Activation Pre and Post Treatment (VAYA-fMRI) [Link]
  7. mproved Academic Performance and Medication Rebound in Patients with ADHD Following the Use of Vayarin®, a Multi-Year, Real-World Retrospective Study [Link]
  8. Pharmacokinetics Basics- Absorption, Distribution, Metabolism and Excretion [Link]
  9. Vaya Direct [Link]
  10. Vayarin product label [Link]
  11. FDA label PS [Link]
  12. Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA [Link]
  13. Drug Insert Vayarin [Link]
External Links
PubChem Substance
347910439
Wikipedia
Vayarin

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentADHD Inattention or Mixed Type / Attention Deficit Disorder With Hyperactivity / Children / Epilepsies1
Not AvailableCompletedNot AvailableAttention Deficit Disorder With Hyperactivity (ADHD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Classification
Not classified

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Pharmacokinetics Basics- Absorption, Distribution, Metabolism and Excretion [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxidoreductase activity
Specific Function
Isoform 2 does not exhibit any catalytic activity toward 20:3n-6, but it may enhance FADS2 activity (By similarity). Isoform 1 is a component of a lipid metabolic pathway that catalyzes biosynthesi...
Gene Name
FADS1
Uniprot ID
O60427
Uniprot Name
Fatty acid desaturase 1
Molecular Weight
51963.945 Da
References
  1. Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Transferase activity
Specific Function
Catalyzes the first and rate-limiting reaction of the four that constitute the long-chain fatty acids elongation cycle. This endoplasmic reticulum-bound enzymatic process, allows the addition of 2 ...
Gene Name
ELOVL4
Uniprot ID
Q9GZR5
Uniprot Name
Elongation of very long chain fatty acids protein 4
Molecular Weight
36828.905 Da
References
  1. Vayarin product label [Link]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Substrate
General Function
Receptor binding
Specific Function
Catalyzes the desaturation of acyl-CoAs to 2-trans-enoyl-CoAs. Isoform 1 shows highest activity against medium-chain fatty acyl-CoAs and activity decreases with increasing chain length. Isoform 2 i...
Gene Name
ACOX1
Uniprot ID
Q15067
Uniprot Name
Peroxisomal acyl-coenzyme A oxidase 1
Molecular Weight
74423.035 Da
References
  1. Dyall SC: Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA. Front Aging Neurosci. 2015 Apr 21;7:52. doi: 10.3389/fnagi.2015.00052. eCollection 2015. [PubMed:25954194]

Drug created on November 17, 2015 12:25 / Updated on September 15, 2019 08:17