Pyrimethamine

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Pyrimethamine
Pyrimethamine2DACS.svg
Pyrimethamine-3D-balls.png
Clinical data
Pronunciation /ˌpɪrˈmɛθəmin/
Trade names Daraprim
AHFS/Drugs.com Monograph
MedlinePlus a601050
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
Oral
ATC code P01BD01 (WHO)
QP51AX51 (WHO) (combinations)
Legal status
Legal status
Pharmacokinetic data
Bioavailability well-absorbed
Protein binding 87%
Metabolism Hepatic
Biological half-life 96 hours
Excretion Renal
Identifiers
Systematic (IUPAC) name: 5-(4-chlorophenyl)-6-ethyl- 2,4-pyrimidinediamine
CAS Number 58-14-0 YesY
PubChem (CID) 4993
IUPHAR/BPS 4800
DrugBank DB00205 YesY
ChemSpider 4819 YesY
UNII Z3614QOX8W YesY
KEGG D00488 YesY
ChEBI CHEBI:8673 YesY
ChEMBL CHEMBL36 YesY
PDB ligand ID CP6 (PDBe, RCSB PDB)
Chemical and physical data
Formula C12H13ClN4
Molar mass 248.71 g/mol
3D model (Jmol) Interactive image
  (verify)

Pyrimethamine, sold under the trade name Daraprim, is a medication used to treat toxoplasmosis, malaria, and cystoisosporiasis.[1] It is also used with dapsone as a second line option to prevent Pneumocystis jiroveci pneumonia (PCP) in people with HIV/AIDS.[1] It is taken by mouth.[1]

Common side effects include loss of appetite, nausea, vomiting, and diarrhea.[2] It can also cause a skin rash and hematologic changes.[3] The medication is classified as a dihydrofolate reductase inhibitor and works by inhibition folic acid metabolism.

Pyrimethamine was discovered in 1952 and come into medical use in 1953.[1][4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] Gertrude Elion at Burroughs-Wellcome (now part of GlaxoSmithKline) developed pyrimethamine with the intention of treating malaria.[6] No manufacturers of the medication are in the United States. Currently, the medication rights are owned by Turing Pharmaceuticals.[7] Turing Pharmaceuticals decided to increase the price, causing a controversy.[8]

Medical uses[edit]

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

It is primarily active against Plasmodium falciparum, but also against Plasmodium vivax.[10] 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 is widely used, such as in Fansidar, though resistance to this combination is increasing.[10] It has been used in the treatment of actinomycosis and isosporiasis, and for the treatment and prevention of Pneumocystis jirovecii pneumonia.[citation needed]

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.

In 2011, researchers discovered that pyrimethamine can increase β-hexosaminidase activity, thus potentially slowing down the progression of late-onset Tay–Sachs disease.[11] It is being evaluated in clinical trials as a treatment for amyotrophic lateral sclerosis.[12]

Pyrimethamine has also been used in several trials to treat retinochoroiditis.[13]

Contraindications[edit]

Pyrimethamine is contraindicated in patients with:[9]

Pregnancy consideration[edit]

Pyrimethamine is labeled as pregnancy category C in the United States.[2] To date, not enough evidence on its risks in pregnancy or its effects on the fetus is available. [2][14]

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.[3][14] A rash, which can be indicative of a hypersensitivity reaction, is also seen, particularly in combination with sulfonamides.[14] Central nervous system effects include ataxia, tremors, and seizures.[3] Hematologic side effects such as thrombocytopenia, leukopenia, and anemia can also occur.[3]

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]

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]

Nobel Prize-winning American scientist Gertrude Elion developed the drug at Burroughs-Wellcome (now part of GlaxoSmithKline) to combat malaria.[6] 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.[7] 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.[22]

Availability and price[edit]

In the United States, as of 2015, with Turing Pharmaceuticals' acquisition of the US marketing rights for Daraprim tablets,[23] Daraprim has become a single-source and specialty pharmacy item, and the price of Daraprim has been increased.[24] The cost of a monthly course for a person on 75 mg dose rose to about $75,000/month, or $750 per tablet.[25][26] 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.[24][27] 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.[27]

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."[28][29] As a result of the backlash, Shkreli hired a crisis public relations firm to help explain his fund's move.[30] 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.[31] 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."[31]

The price increase has been fiercely criticised by physician groups such as HIV Medicine Associates and Infectious Diseases Society of America.[32]

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.[33][34]

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).[35][36][37][38]

In the UK, the same drug is available from GSK at a cost of US$20 (£13) for 30 tablets (about $0.66 each).[39]

In Australia, the drug is available in most pharmacists at a cost of US$9.35 (A$12.99) for 50 tablets (around US$0.18 each).[40]

In Brazil, the drug is available for R$0.07 a pill, or about US$0.02.[41]

In Canada, the drug was reportedly discontinued in 2013, but hospitals may make the drug in-house when it is needed.[42] As of December 2015, Daraprim imported into Canada directly from GSK UK is available from an online pharmacy for US$2.20 per tablet.[43]

On October 22, 2015, Imprimis Pharmaceuticals announced it has made available compounded and customizable formulations of pyrimethamine and leucovorin in oral capsules starting as low as $99.00 for a 100-count bottle in the United States.[44]

See also[edit]

References[edit]

  1. ^ a b c d "Pyrimethamine". The American Society of Health-System Pharmacists. Retrieved 2 December 2016. 
  2. ^ a b c "Daraprim - FDA prescribing information, side effects and uses". www.drugs.com. Retrieved 2016-11-07. 
  3. ^ a b c d "Daraprim Side Effects in Detail - Drugs.com". www.drugs.com. Retrieved 2016-11-07. 
  4. ^ Sylvie, Manguin; Pierre, Carnevale; Jean, Mouchet (2008). Biodiversity of Malaria in the world. John Libbey Eurotext. p. 6. ISBN 9782742009633. 
  5. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  6. ^ a b Vasudevan, D.M.; Sreekumari, S.; Vaidyanathan, Kannan (2013). Textbook of Biochemistry for Medical Students. JP Medical Ltd. p. 491. ISBN 9789350905302. OCLC 843532694. Retrieved January 15, 2016. 
  7. ^ a b John LaMattina (2015-09-21). "Here's A Way For Pharma To Prevent Outrageous Generic Price Increases -- And Help Its Reputation". Forbes. 
  8. ^ Mullin, Emily. "Turing Pharma Says Daraprim Availability Will Be Unaffected By Shkreli Arrest". Forbes. Retrieved 2016-11-10. 
  9. ^ a b c Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  10. ^ a b Brayfield, A, ed. (13 December 2013). "Pyrimethamine". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 12 April 2014. 
  11. ^ Osher, E; Fattal-Valevski, A; Sagie, L; Urshanski, N; Amir-Levi, Y; Katzburg, S; Peleg, L; Lerman-Sagie, T; Zimran, A; Elstein, D; Navon, R; Stern, N; Valevski, A (March 2011). "Pyrimethamine increases β-hexosaminidase A activity in patients with Late Onset Tay Sachs.". Molecular Genetics and Metabolism. 102 (3): 356–63. doi:10.1016/j.ymgme.2010.11.163. PMID 21185210. 
  12. ^ "Pyrimethamine ALS trial". 
  13. ^ Pradhan E, Bhandari S, Gilbert RE, Stanford M (2016). "Antibiotics versus no treatment for toxoplasma retinochoroiditis". Cochrane Database Syst Rev. 5: CD002218. doi:10.1002/14651858.CD002218.pub2. PMID 27198629. 
  14. ^ a b c "Pyrimethamine | FDA Label - Tablet | AIDSinfo". AIDSinfo. Retrieved 2016-11-07. 
  15. ^ a b "PRODUCT INFORMATION DARAPRIM TABLETS". TGA eBusiness Services. Aspen Pharmacare Australia Pty Ltd. 5 December 2011. p. 1. Retrieved 12 April 2014. 
  16. ^ Limpert, AS; Mattmann, ME; Cosford, ND (2013). "Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)." (PDF). Beilstein Journal of Organic Chemistry. 9: 717–32. doi:10.3762/bjoc.9.82. PMC 3678841Freely accessible. PMID 23766784. 
  17. ^ Lange, DJ; Andersen, PM; Remanan, R; Marklund, S; Benjamin, D (April 2013). "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. doi:10.3109/17482968.2012.724074. PMID 22985433. 
  18. ^ Gatton M.L.; et al. (2004). "Evolution of resistance to sulfadoxine-pyrimethamine in Plasmodium falciparum". Antimicrob Agents Chemother. 48 (6): 2116–23. doi:10.1128/AAC.48.6.2116-2123.2004. PMC 415611Freely accessible. PMID 15155209. 
  19. ^ Sirichaiwat C, et al. (2004). "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". J Med Chem. 47 (2): 345–54. doi:10.1021/jm0303352. PMID 14711307. 
  20. ^ Ariana Eunjung Cha (2015-09-22). "CEO who raised price of old pill more than $700 calls journalist a 'moron' for asking why". The Washington Post. 
  21. ^ Pollack, Andrew (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". New York Times. Retrieved 17 December 2015. 
  22. ^ Kliff, Sarah (September 22, 2015). "Vox Explainers: A Drug Company Raised a Pill's Price 5,500 Percent Because, in America, It Can". Vox (online). Retrieved December 9, 2015. 
  23. ^ Turing Pharmaceuticals AG Turing Pharmaceuticals AG Acquires U.S. Marketing Rights to DARAPRIM® (pyrimethamine) 10 August 2015, PR Newswire Association LLC
  24. ^ a b Monica V. Mahoney New Pyrimethamine Dispensing Program: What Pharmacists Should Know PharmacyTimes, July 17, 2015
  25. ^ ANDREW POLLACK (20 September 2015). "Drug Goes From $13.50 a Tablet to $750, Overnight". Retrieved 21 September 2015. 
  26. ^ "WATCH: Ex-hedge funder who hiked AIDS pill cost by 5,500 percent says drug 'still underpriced'". RawStory.com. Retrieved 22 September 2015. 
  27. ^ a b "The Most Unconscionable Drug Price Hike I Have Yet Seen", by Derek Lowe, September 11, 2014, In the Pipeline.
  28. ^ Ramsey, Lydia (22 Sep 2015). "A pharma CEO tried to defend his decision to jack up the price of a critical drug by 5,000% — and it backfired". Business Insider. 
  29. ^ Reuters (22 Sep 2015). "Company hikes price of popular drug". Reuters. 
  30. ^ Tannahill, Jason (9 Oct 2015). "PR Man Allan Ripp Representing The "Most Hated Man in America"". EverythingPR. 
  31. ^ a b Pollack, Andrew (24 November 2015). "Turing Refuses to Lower List Price of Toxoplasmosis Drug". New York Times. Retrieved 25 November 2015. 
  32. ^ http://www.hivma.org/uploadedFiles/HIVMA/HomePageContent/PyrimethamineLetterFINAL.pdf
  33. ^ Davey, Melissa (December 1, 2016). "Australian students recreate Martin Shkreli price-hike drug in school lab". The Guardian. Retrieved December 1, 2016. 
  34. ^ Dunlop, Greg (1 December 2016). "Australian boys recreate life-saving drug". BBC News. Retrieved 1 December 2016. 
  35. ^ "MEDLINE INDIA - SULFADOXINE WITH PYRIMETHAMINE". www.medlineindia.com. Retrieved 2015-09-22. 
  36. ^ "It is Cheaper for an American patient to fly out to India and buy a year's supply of the medication than buy a single Daraprim tablet in the US". 
  37. ^ "There is no reason why the United States cannot have as vigorous a market in generic pharmaceuticals as does India". 
  38. ^ "High Drug Prices: Should We Blame Pharma Or The FDA?". 
  39. ^ "What's a fair price for a drug?". BBC News. Retrieved 2015-09-23. 
  40. ^ "Chemist Warehouse". www.chemistwarehouse.com.au. Retrieved 2015-12-12. 
  41. ^ "Remédio que teve aumento de 5.000% nos EUA custa R$ 0,07 no Brasil (e não vai aumentar)". brasilpost.com.br. Retrieved 2015-09-23. 
  42. ^ "Turing CEO to roll back 5,000% price hike for Daraprim pills". 
  43. ^ "Daraprim 25mg and/or Equivalents". Retrieved 2015-12-18. 
  44. ^ "Imprimis Pharmaceuticals to Make Compounded and Customizable Formulation of Pyrimethamine and Leucovorin Available for Physicians to Prescribe for their Patients as an Alternative to Daraprim® - Oct 22, 2015". imprimispharma.investorroom.com. Retrieved 2015-10-23. 

External links[edit]