Pyrimethamine

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Pyrimethamine
Pyrimethamine2DACS.svg
Pyrimethamine-3D-balls.png
Clinical data
Pronunciation /ˌpɪrɪˈmɛθəmin/
Trade names Daraprim
AHFS/Drugs.com Monograph
MedlinePlus a601050
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability well-absorbed
Protein binding 87%
Metabolism Liver
Biological half-life 96 hours
Excretion Kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
ECHA InfoCard 100.000.331
Chemical and physical data
Formula C12H13ClN4
Molar mass 248.71 g/mol
3D model (JSmol)
Melting point 233 to 234 °C (451 to 453 °F)
  (verify)

Pyrimethamine, sold under the trade name Daraprim, is a medication used with leucovorin to treat toxoplasmosis and cystoisosporiasis.[1][2] It is also used with dapsone as a second line option to prevent Pneumocystis jiroveci pneumonia (PCP) in people with HIV/AIDS.[1] It was previously used for malaria but is no longer recommended due to resistance.[1] Pyrimethamine is taken by mouth.[1]

Common side effects include gastrointestinal upset, severe allergic reactions, bone marrow suppression.[1] It should not be used by people with folate deficiency that has resulted in anemia.[1] There is concern that it may increase the risk of cancer.[1] While occasionally used in pregnancy it is unclear if pyrimethamine is safe for the baby.[3] Pyrimethamine is classified as a folic acid antagonist.[1] It works by inhibiting folic acid metabolism and therefore the making of DNA.[1]

Pyrimethamine was discovered in 1952 and came into medical use in 1953.[1][4] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[5] In the United States in 2015 it was not available as a generic medication and the price was increased from 13.50 USD to 750 USD a tablet (75,000 USD for a course of treatment).[6][2][7] In other areas of the world it is available as a generic and costs as little as 0.05 to 0.10 USD per dose.[8]

Medical uses[edit]

Pyrimethamine is typically given with a sulfonamide and folinic acid.[9]

It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.[citation needed]

Toxoplasmosis[edit]

Pyrimethamine is also used in combination with sulfadiazine to treat active toxoplasmosis. The two drugs bind the same enzymatic targets as the drugs trimethoprim and sulfamethoxazole - dihydrofolate reductase and dihydropteroate synthase, respectively.

Pyrimethamine has also been used in several trials to treat retinochoroiditis.[10]

Pregnancy consideration[edit]

Pyrimethamine is labeled as pregnancy category C in the United States.[11] To date, not enough evidence on its risks in pregnancy or its effects on the fetus is available. [11][12]

Malaria[edit]

It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax.[13] Due to the emergence of pyrimethamine-resistant strains of P. falciparum, pyrimethamine alone is seldom used now. In combination with a long-acting sulfonamide such as sulfadiazine, it was widely used, such as in Fansidar, though resistance to this combination is increasing.[13]

Contraindications[edit]

Pyrimethamine is contraindicated in people with folate-deficiency anaemia[9]

Side effects[edit]

When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea.[14][12] A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides.[12] Central nervous system effects include ataxia, tremors, and seizures.[14] Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.[14]

Interactions[edit]

Other antifolate agents such as methotrexate and trimethoprim may potentiate the antifolate actions of pyrimethamine, leading to potential folate deficiency, anaemia, and other blood dyscrasias.[9]

Mechanism of action[edit]

Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase.[15] Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa.[15] Pyrimethamine has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.[16][17]

Other medications[edit]

Pyrimethamine is typically given with folinic acid and sulfadiazine.

Mechanism of resistance[edit]

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.[18] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[19]

History[edit]

Synthesis of pyrimethamine typically begins with p-chlorophenylacetonitrile, which undergoes a condensation reaction with ethyl propionate ester; the product of this then reacts with diazomethane to form an enol ether, which reacts with free guanidine in a second condensation reaction.

Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria.[20] Pyrimethamine has been available since 1953.[21] In 2010, GlaxoSmithKline sold the marketing rights for Daraprim to CorePharma. Impax Laboratories sought to buy CorePharma in 2014, and completed the acquisition, including Daraprim, in March 2015.[22] In August 2015, the rights were bought by Turing Pharmaceuticals.[23] Turing subsequently became known for a price hike controversy when it raised the price of a dose of the drug in the U.S. market from US$13.50 to US$750, a 5,500% increase.[24]

Availability and price[edit]

In the United States, as of 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets,[25] Daraprim has become a single-source and specialty pharmacy item, and the price of Daraprim has been increased.[26] The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month, or $750 per tablet.[27][28] Outpatients can no longer obtain Daraprim from their community pharmacy, but only through a single dispensing pharmacy, Walgreens Specialty Pharmacy, and institutions can no longer order from their general wholesaler, but have to set up an account with the Daraprim Direct program.[26][29] Presentations from Retrophin, a company formerly headed by Martin Shkreli, CEO of Turing, from which Turing acquired the rights to Daraprim, suggest that a closed distribution system could prevent generic competitors from legally obtaining the drugs for the bioequivalence studies required for FDA approval of a generic drug.[29]

Martin Shkreli, CEO of Turing, defended the price hike by saying, "If there was a company that was selling an Aston Martin at the price of a bicycle, and we buy that company and we ask to charge Toyota prices, I don't think that that should be a crime."[30][31] As a result of the backlash, Shkreli hired a crisis public relations firm to help explain his fund's move.[32] Turing Pharmaceuticals announced on November 24, 2015, "that it would not reduce the list price of that drug after all", but they will offer various patient assistance programs.[33] However, New York Times journalist Andrew Pollack noted that these programs "are standard for companies selling extremely high-priced drugs. They enable the patients to get the drug while pushing most of the costs onto insurance companies and taxpayers."[33]

The price increase has been fiercely criticised by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.[34]

In 2016, a group of high school students from Sydney Grammar supported by the University of Sydney prepared pyrimethamine as an illustration that the synthesis is comparatively easy and the price-hike unjustifiable. Shkreli said the schoolboys were not competition, likely because the necessary bioequivalence studies require a sample of the existing medication provided directly by the company, and not simply purchased from a pharmacy, which Turing could decline to provide.[35][36]

In India, over a dozen pharmaceutical companies manufacture and sell pyrimethamine tablets, and multiple combinations of generic pyrimethamine are available for a price ranging from US$0.04 to US$0.10 each (3–7 rupees).[37][38][39][8]

In the UK, the same drug is available from GSK at a cost of US$20 (£13) for 30 tablets (about $0.66 each).[40]

In Australia, the drug is available in most pharmacies at a cost of US$9.35 (A$12.99) for 50 tablets (around US$0.18 each).[41]

In Brazil, the drug is available for R$0.07 a pill, or about US$0.02.[42]

In Canada, the drug was reportedly discontinued in 2013, but hospitals may make the drug in-house when it is needed.[43] As of December 2015, Daraprim imported into Canada directly from GSK UK is available from an online pharmacy for US$2.20 per tablet.[44]

In Switzerland, the drug is available for US$9.45 (CHF9.05) for 30 tablets (around US$0.32 a piece).[45]

On October 22, 2015, Imprimis Pharmaceuticals announced it has made available compounded and customizable formulations of pyrimethamine and leucovorin in capsules to be taken by mouth starting as low as $99.00 for a 100-count bottle in the United States.[46]

Research[edit]

In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.[47] It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.[48]

References[edit]

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External links[edit]