Chemistry:Pyrimethamine

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Short description: Medication
Pyrimethamine
Pyrimethamine2DACS.svg
Pyrimethamine-from-xtal-3D-bs-17.png
Clinical data
Pronunciation/ˌpɪrɪˈmɛθəmɪn/
Trade namesDaraprim, others
AHFS/Drugs.comMonograph
MedlinePlusa601050
License data
Pregnancy
category
Routes of
administration		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilitywell-absorbed
Protein binding87%
MetabolismLiver
Elimination half-life96 hours
ExcretionKidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC12H13ClN4
Molar mass248.71 g·mol−1
3D model (JSmol)
Melting point233 to 234 °C (451 to 453 °F)
  (verify)

Pyrimethamine, sold under the brand name Daraprim among others, is a medication used with leucovorin (leucovorin is used to decrease side effects of pyrimethamine; it does not have intrinsic anti-parasitic activity) to treat the parasitic diseases toxoplasmosis and cystoisosporiasis.[3][4] It is also used with dapsone as a second-line option to prevent Pneumocystis jiroveci pneumonia in people with HIV/AIDS.[3] It was previously used for malaria but is no longer recommended due to resistance.[3] Pyrimethamine is taken by mouth.[3]

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

Pyrimethamine was discovered in 1952 and came into medical use in 1953.[3][5] It is on the World Health Organization's List of Essential Medicines.[6] It was approved as a generic in the United States in February 2020.[7]

Medical uses

Pyrimethamine is typically given with a sulfonamide and folinic acid.[8]

It is used for the treatment of toxoplasmosis, actinomycosis, and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.[3]

Toxoplasmosis

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.[citation needed]

Pyrimethamine has also been used in several trials to treat retinochoroiditis.[9]

Pregnancy consideration

Pyrimethamine is labeled as pregnancy category C in the United States.[1][10] To date, not enough evidence on its risks in pregnancy or its effects on the fetus is available.[10][11]

Malaria

It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax.[12] 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.[12]

Contraindications

Pyrimethamine is contraindicated in people with folate-deficiency anaemia.[8]

Side effects

When higher doses are used, as in the treatment of toxoplasmosis, pyrimethamine can cause gastrointestinal symptoms such as nausea, vomiting, glossitis, anorexia, and diarrhea.[11][13] A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides.[11] Central nervous system effects include ataxia, tremors, and seizures.[13] Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.[13]

Interactions

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.[8]

Mechanism of action

Pyrimethamine interferes with the regeneration of tetrahydrofolic acid from dihydrofolate by competitively inhibiting the enzyme dihydrofolate reductase.[14] Tetrahydrofolic acid is essential for DNA and RNA synthesis in many species, including protozoa.[14] It has also been found to reduce the expression of SOD1, a key protein involved in amyotrophic lateral sclerosis.[15][16]

Other medications

Pyrimethamine is typically given with folinic acid and sulfadiazine.[10]

  • Sulfonamides (e.g. sulfadiazine) inhibit dihydropteroate synthetase, an enzyme that participates in folic acid synthesis from para-aminobenzoic acid. Hence, sulfonamides work synergistically with pyrimethamine by blocking a different enzyme needed for folic acid synthesis.
  • Folinic acid (leucovorin) is a folic acid derivative converted to tetrahydrofolate, the primary active form of folic acid, in vivo, without relying on dihydrofolate reductase. Folinic acid reduces side effects related to folate deficiency in the patient.

Mechanism of resistance

Resistance to pyrimethamine is widespread. Mutations in the malarial gene for dihydrofolate reductase may reduce its effectiveness.[17] These mutations decrease the binding affinity between pyrimethamine and dihydrofolate reductase via loss of hydrogen bonds and steric interactions.[18]

History

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.[19] Pyrimethamine has been available since 1953.[20] 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.[21] In August 2015, the rights were bought by Turing Pharmaceuticals.[22] Turing subsequently became infamous 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.[23]

Society and culture

Economics

In the United States in 2015, Turing Pharmaceuticals was criticized for increasing the price 50-fold, from US$13.50 to $750 a tablet,[24] leading to a cost of $75,000 for a course of treatment reported at one hospital.[25]

United States

In the United States, in 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets,[26] Daraprim became a single-source and specialty pharmacy item, and the price was increased.[27] The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month at one hospital, or $750 per tablet while it was previously priced at $13.50.[28]

Outpatients could no longer obtain the medication from a community pharmacy, but only through a single dispensing pharmacy, Walgreens Specialty Pharmacy, and institutions could no longer order from their general wholesaler, but had to set up an account with the Daraprim Direct program.[27][29] Presentations from Retrophin, a company formerly headed by Martin Shkreli, CEO of Turing, from which Turing acquired the rights to Daraprim, suggested 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]

Shkreli 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 24 November 2015, "that it would not reduce the list price of that drug after all", but they would offer patient assistance programs.[33] 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 was criticized 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. His team produced 3.7 g for US$20, which would have been worth between US$35,000 and US$110,000 in the United States at the time.[35] 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.[36][37] Nonetheless, the students' work was featured in The Guardian [36] and Time (magazine) magazine,[38] and on ABC Australia,[35] the BBC,[37] and CNN.[39]

On 22 October 2015, Imprimis Pharmaceuticals announced it had made available compounded and customizable formulations of pyrimethamine and leucovorin in capsules to be taken by mouth starting as low as $99 for a 100-count bottle in the United States.[40] Pyrimethamine was approved as a generic in the United States in February 2020.[7]

In January 2020, the FTC filed a case against Vyera "alleging an elaborate anticompetitive scheme to preserve a monopoly for the life-saving drug, Daraprim".[41] A settlement was reached in December 2021. According to AP News, the settlement "requires Vyera and Phoenixus to provide up to $40 million in relief over 10 years to consumers who allegedly were fleeced by their actions and requires them to make Daraprim available to any potential generic competitor at the cost of producing the drug."[42] According to Law360, company executive Kevin Mulleady "agreed to a seven-year ban on working for or holding more than an 8% share in most pharmaceutical companies."[43]

Other countries

In India, multiple combinations of generic pyrimethamine are available for a price ranging from US$0.04 to US$0.10 each (3–7 rupees).[44][45][46][47]

In the UK, the same drug is available from GSK at a cost of US$20 (£13) for 30 tablets (about $0.66 each).[48]

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).[49]

In Brazil , the drug is available for R$0.07 a pill, or about US$0.02.[50]

In Switzerland , the drug is available for US$9.45 (CHF9.05) for 30 tablets (around US$0.32 a piece).[51]

Research

In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.[52] It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.[53]

See also

  • Sulfadoxine/pyrimethamine

References

  1. ↑ 1.0 1.1 1.2 "Pyrimethamine (Daraprim) Use During Pregnancy". 31 July 2019. https://www.drugs.com/pregnancy/pyrimethamine.html. 
  2. ↑ "Daraprim Tablets – Summary of Product Characteristics (SmPC)". 19 February 2020. https://www.medicines.org.uk/emc/product/938/smpc. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 "Pyrimethamine". The American Society of Health-System Pharmacists. https://www.drugs.com/monograph/pyrimethamine.html. 
  4. ↑ Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. 2015. p. 54. ISBN 9781284057560. 
  5. ↑ (in en) Biodiversity of Malaria in the world. John Libbey Eurotext. 2008. p. 6. ISBN 9782742009633. https://books.google.com/books?id=Sk0JBAAAQBAJ&pg=PA6. Retrieved 10 September 2017. 
  6. ↑ World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. 2019. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO. 
  7. ↑ 7.0 7.1 "FDA Approves First Generic of Daraprim". U.S. Food and Drug Administration (FDA) (Press release). 28 February 2020. Archived from the original on 29 February 2020. Retrieved 28 February 2020.
  8. ↑ 8.0 8.1 8.2 Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. 2013. ISBN 978-0-9805790-9-3. 
  9. ↑ "Antibiotics versus no treatment for toxoplasma retinochoroiditis". The Cochrane Database of Systematic Reviews 2016 (5): CD002218. May 2016. doi:10.1002/14651858.CD002218.pub2. PMID 27198629. 
  10. ↑ 10.0 10.1 10.2 "Daraprim- pyrimethamine tablet". 31 August 2017. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5368616d-6520-6f6e-2053-686b72656c69. 
  11. ↑ 11.0 11.1 11.2 "Pyrimethamine | FDA Label - Tablet". https://aidsinfo.nih.gov/drugs/445/pyrimethamine/0/professional#LINK_cdcdcf89-7c83-4eec-8b1c-a99ee17b39ea. 
  12. ↑ 12.0 12.1 "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. 13 December 2013. http://www.medicinescomplete.com/mc/martindale/current/1389-y.htm. 
  13. ↑ 13.0 13.1 13.2 "Daraprim Side Effects in Detail". https://www.drugs.com/sfx/daraprim-side-effects.html. 
  14. ↑ 14.0 14.1 "Product Information Daraprim Tablets". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01016-1. 
  15. ↑ "Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)". Beilstein Journal of Organic Chemistry 9: 717–732. 2013. doi:10.3762/bjoc.9.82. PMID 23766784. PMC 3678841. http://www.beilstein-journals.org/bjoc/content/pdf/1860-5397-9-82.pdf. 
  16. ↑ "Pyrimethamine decreases levels of SOD1 in leukocytes and cerebrospinal fluid of ALS patients: a phase I pilot study". Amyotrophic Lateral Sclerosis & Frontotemporal Degeneration 14 (3): 199–204. April 2013. doi:10.3109/17482968.2012.724074. PMID 22985433. 
  17. ↑ "Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum". Antimicrobial Agents and Chemotherapy 48 (6): 2116–2123. June 2004. doi:10.1128/AAC.48.6.2116-2123.2004. PMID 15155209. 
  18. ↑ "Target guided synthesis of 5-benzyl-2,4-diamonopyrimidines: their antimalarial activities and binding affinities to wild type and mutant dihydrofolate reductases from Plasmodium falciparum". Journal of Medicinal Chemistry 47 (2): 345–354. January 2004. doi:10.1021/jm0303352. PMID 14711307. 
  19. ↑ Textbook of Biochemistry for Medical Students. JP Medical Ltd. 2013. p. 491. ISBN 9789350905302. OCLC 843532694. https://books.google.com/books?id=nQz8AAAAQBAJ&pg=PA491. Retrieved 15 January 2016. 
  20. ↑ "CEO who raised price of old pill more than $700 calls journalist a 'moron' for asking why". The Washington Post. 2015-09-22. https://www.washingtonpost.com/news/to-your-health/wp/2015/09/21/ceo-of-company-that-raised-the-price-of-old-pill-hundreds-of-dollars-overnight-calls-journalist-a-moron-for-asking-why/. 
  21. ↑ "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. 20 September 2015. https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html. 
  22. ↑ "Here's A Way For Pharma To Prevent Outrageous Generic Price Increases – And Help Its Reputation". Forbes. 2015-09-21. https://www.forbes.com/sites/johnlamattina/2015/09/21/heres-a-way-for-pharma-to-prevent-outrageous-generic-price-increases-and-help-its-reputation/. 
  23. ↑ "Vox Explainers: A Drug Company Raised a Pill's Price 5,500 Percent Because, in America, It Can". 22 September 2015. https://www.vox.com/2015/9/22/9366721/daraprim-price-shkreli-turing. 
  24. ↑ "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. 20 September 2015. https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html. "Turing immediately raised the price to $750 a tablet from $13.50, bringing the annual cost of treatment for some patients to hundreds of thousands of dollars." 
  25. ↑ "Essential Medicines in the United States--Why Access Is Diminishing". The New England Journal of Medicine 374 (20): 1904–1907. May 2016. doi:10.1056/nejmp1601559. PMID 27192669. "Heavy scrutiny followed, and although Turing agreed to reduce the price, the drug remains prohibitively expensive for many patients. Recently, at our hospital, an immigrant patient with a new diagnosis of HIV– AIDS and toxoplasmosis couldn’t receive first-line therapy because of cost: the price for 100 pills was $75,000.". 
  26. ↑ "Turing Pharmaceuticals AG Acquires U.S. Marketing Rights to Daraprim (pyrimethamine)". Turing Pharmaceuticals AG. PR Newswire Association LLC. 10 August 2015. http://www.prnewswire.com/news-releases/turing-pharmaceuticals-ag-acquires-us-marketing-rights-to-daraprim-pyrimethamine-300125853.html. 
  27. ↑ 27.0 27.1 "New Pyrimethamine Dispensing Program: What Pharmacists Should Know". PharmacyTimes. 17 July 2015. https://www.pharmacytimes.com/view/new-pyrimethamine-dispensing-program-what-pharmacists-should-know. 
  28. ↑ "Drug Goes From $13.50 a Tablet to $750, Overnight". The New York Times. 20 September 2015. https://www.nytimes.com/2015/09/21/business/a-huge-overnight-increase-in-a-drugs-price-raises-protests.html?ref=health&_r=0. 
  29. ↑ 29.0 29.1 "The Most Unconscionable Drug Price Hike I Have Yet Seen". In the Pipeline. 11 September 2014. https://www.science.org/content/blog-post/most-unconscionable-drug-price-hike-i-have-yet-seen. 
  30. ↑ "A pharma CEO tried to defend his decision to jack up the price of a critical drug by 5,000% – and it backfired". Business Insider. 22 Sep 2015. http://www.businessinsider.com/martin-shkreli-defends-daraprim-price-2015-9. 
  31. ↑ "Company hikes price of popular drug". Reuters. 22 Sep 2015. http://uk.reuters.com/video/2015/09/22/company-hikes-price-of-popular-drug?videoId=365682609. 
  32. ↑ "PR Man Allan Ripp Representing The "Most Hated Man in America"". EverythingPR. 9 Oct 2015. http://everything-pr.com/allan-ripp-represents-martin-shkreli/69517/. 
  33. ↑ 33.0 33.1 "Turing Refuses to Lower List Price of Toxoplasmosis Drug". New York Times. 24 November 2015. https://www.nytimes.com/2015/11/25/business/turing-refuses-to-lower-list-price-of-toxoplasmosis-drug.html?smid=tw-nytimes&smtyp=cur. 
  34. ↑ "Letter to Tom Evegan and Kevin Burnier". http://www.hivma.org/uploadedFiles/HIVMA/HomePageContent/PyrimethamineLetterFINAL.pdf. 
  35. ↑ 35.0 35.1 "Daraprim drug's key ingredient recreated by high school students in Sydney for just $20". ABC News. 30 November 2016. https://www.abc.net.au/news/2016-11-30/daraprim-nsw-students-create-drug-martin-shkreli-sold/8078892. 
  36. ↑ 36.0 36.1 "Australian students recreate Martin Shkreli price-hike drug in school lab". The Guardian. 1 December 2016. https://www.theguardian.com/science/2016/dec/01/australian-students-recreate-martin-shkreli-price-hike-drug-in-school-lab. 
  37. ↑ 37.0 37.1 "Australian boys recreate life-saving drug". BBC News. 1 December 2016. https://www.bbc.com/news/world-australia-38153254. 
  38. ↑ "Watch Martin Shkreli Respond to the School Kids Who Recreated His Drug for $2 a Dose". Time (magazine). 2 December 2016. http://time.com/4588458/martin-shkreli-response-sydney-students-daraprim/. Retrieved 23 April 2019. 
  39. ↑ "'Pharma Bro' Martin Shkreli meets his match in a group of Australian schoolboys". CNN. 1 December 2016. https://edition.cnn.com/2016/12/01/health/daraprim-oz/index.html. 
  40. ↑ "Express Scripts, Imprimis to offer $1 Daraprim alternative". December 2015. https://www.cnbc.com/2015/11/30/express-scripts-imprimis-to-offer-daraprim-alternative.html. 
  41. ↑ "Vyera Pharmaceuticals, LLC". January 27, 2020. https://www.ftc.gov/enforcement/cases-proceedings/161-0001/vyera-pharmaceuticals-llc. 
  42. ↑ "'Pharma Bro' firm reaches $40M settlement in gouging case". December 8, 2021. https://apnews.com/article/business-health-federal-trade-commission-martin-shkreli-98e0a8b6be3dc6901153610756cbb58a. 
  43. ↑ "Former Shkreli Co. Inks Deal Worth Up To $40M With FTC, AGs - Law360". December 7, 2021. https://www.law360.com/articles/1446580/former-shkreli-co-inks-deal-worth-up-to-40m-with-ftc-ags. 
  44. ↑ "High Drug Prices: Should We Blame Pharma Or The FDA?". Clinical Leader. 29 September 2015. http://www.clinicalleader.com/doc/high-drug-prices-should-we-blame-pharma-or-the-fda-0001. 
  45. ↑ "Medline India – Sulfadoxine with Pyrimethamine". http://www.medlineindia.com/antibiotic/sulfadoxine_with_pyrimethamine.htm. 
  46. ↑ "It is Cheaper for an American patient to fly out to India and buy a year's supply of the medication than buy a single Daraprim tablet in the US". 25 September 2015. http://www.ibtimes.co.uk/daraprim-like-drug-costs-less-0-07-india-1521144. 
  47. ↑ "There is no reason why the United States cannot have as vigorous a market in generic pharmaceuticals as does India". 24 September 2015. http://marginalrevolution.com/marginalrevolution/2015/09/generic-drug-regulation.html. 
  48. ↑ "What's a fair price for a drug?". BBC News. 22 September 2015. https://www.bbc.com/news/health-34322720. 
  49. ↑ "Chemist Warehouse". http://www.chemistwarehouse.com.au/Buy/56166/Daraprim-25mg-Tablets-50. 
  50. ↑ "Remédio que teve aumento de 5.000% nos EUA custa R$ 0,07 no Brasil (e não vai aumentar)". http://www.brasilpost.com.br/2015/09/23/remedio-aumento-daraprim_n_8186462.html. 
  51. ↑ "Swiss Compendium information about Daraprim". http://compendium.ch/prod/daraprim-cpr-25-mg/fr. 
  52. ↑ "Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs". Molecular Genetics and Metabolism 102 (3): 356–363. March 2011. doi:10.1016/j.ymgme.2010.11.163. PMID 21185210. 
  53. ↑ Clinical trial number NCT01083667 for "SOD1 Inhibition by Pyrimethamine in Familial Amyotrophic Lateral Sclerosis (ALS)" at ClinicalTrials.gov

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