Tenofovir
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| Tenofovir (top) and tenofovir disoproxil fumarate (bottom) | |
| Systematic (IUPAC) name | |
| ({[(2R)-1-(6-amino-9H-purin-9-yl)propan-2-yl]oxy}methyl)phosphonic acid | |
| Clinical data | |
| Trade names | Viread |
| AHFS/Drugs.com | monograph |
| MedlinePlus | a602018 |
| Pregnancy cat. | B (United States) |
| Legal status | ℞-only (U.S.), POM (UK) |
| Routes | Oral |
| Pharmacokinetic data | |
| Bioavailability | 25% |
| Protein binding | < 1% |
| Half-life | 17 hours |
| Excretion | Renal |
| Identifiers | |
| CAS number | 147127-20-6  |
| ATC code | J05AF07 |
| PubChem | CID 464205 |
| DrugBank | DB00300 |
| ChemSpider | 408154 |
| UNII | 99YXE507IL |
| KEGG | D01982 |
| ChEMBL | CHEMBL483 |
| NIAID ChemDB | 080741 |
| Chemical data | |
| Formula | C9H14N5O4P |
| Mol. mass | 287.213 g/mol |
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Tenofovir disoproxil fumarate (TDF or PMPA[1]), marketed by Gilead Sciences under the trade name Viread, belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors (NRTIs), which block reverse transcriptase, a crucial virus enzyme in human immunodeficiency virus 1 (HIV-1) and hepatitis B virus infections.[2]
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Drug forms [edit]
Tenofovir disoproxil fumarate is a prodrug form of tenofovir. It is also marketed under the brand name Reviro by DRL. Tenofovir is also available in a fixed-dose combination with emtricitabine in a product with the brand name Truvada for once-a-day dosing. Atripla, a fixed-dose triple combination of tenofovir, emtricitabine and efavirenz, was approved by the FDA on 12 July 2006 and is now available, providing a single daily dose for the treatment of HIV.
History [edit]
Tenofovir was discovered through a collaborative research effort between Antonín Holý at the Institute of Organic Chemistry and Biochemistry (IOCB), Academy of Sciences of the Czech Republic (AS CR) in Prague, and Erik DeClercq, Rega Institute for Medical Research, Catholic University of Leuven, Belgium.
Tenofovir was approved by the U.S. Food and Drug Administration (FDA) on October 26, 2001 for the treatment of HIV, and on August 11, 2008 for the treatment of chronic hepatitis B.[3][4]
Increased yield [edit]
A difficult step in the manufacture of tenofovir is near the end, when the mixture is "like oatmeal, making it very difficult to stir," said Joseph Fortunak, who left Abbott Laboratories to teach at Howard. That slows the next reaction, a problem because the intermediary is highly unstable and decomposes, thus lowering the yield.
Fortunak's graduate student Adrian Williams tested different methods to improve this step. A catalyst, TBAB (tetrabutylammonium bromide) sped up the reaction and thinned the oatmeal-like mixture into something "like milk," Williams said. But unexpectedly, it made the product more stable, which substantially increased the yield. This lowered the cost by about 20%.[5]
Indications [edit]
- HIV-1 infection: Tenofovir is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 2 years of age and older.[2] This indication is based on analyses of plasma HIV-1 RNA levels and CD4 cell counts in controlled studies of tenofovir in treatment-naive and treatment-experienced adults. There are no study results demonstrating the effect of tenofovir on the clinical progression of HIV.
- Tenofovir is indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older.[2]
Adverse effects and drug interactions [edit]
The most common side effects associated with tenofovir include nausea, vomiting, diarrhea, and asthenia. Less frequent side effects include hepatotoxicity, abdominal pain, and flatulence.[6] Tenofovir has also been implicated in causing renal toxicity, particularly at elevated concentrations.[7]
Tenofovir can cause acute renal failure, Fanconi syndrome, proteinuria or tubular necrosis. These side effects are due to accumulation of the drug in proximal tubules. Tenofovir can interact with didanosine by increasing didanosine's concentration. It also decreases the concentration of atazanavir sulfate.
Therapeutic drug monitoring [edit]
Tenofovir may be measured in plasma by liquid chromatography. Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in patients with renal or hepatic impairment.[8][9][10]
HIV risk reduction [edit]
A Cochrane review examined the use of tenofovir as a pre-exposure prophylaxis against HIV infection. It found that both tenofovir alone, as well as the tenofovir/emtricitabine combination, significantly decreased the risk of contracting HIV.[11]
References [edit]
- ^ Emau P, Jiang Y, Agy MB et al. (2006). "Post-exposure prophylaxis for SIV revisited: Animal model for HIV infection". AIDS Res Ther 3: 29. doi:10.1186/1742-6405-3-29. PMC 1687192. PMID 17132170.
- ^ a b c Gilead Sciences, Inc. Prescribing Information. Revised: November 2012.
- ^ FDA letter of approval (regarding treatment of hepatitis B)
- ^ FDA Clears Viread for Hepatitis B
- ^ SCHOOFS, MARK (MAY 13, 2011). "Researchers Manipulate Drug's Chemistry in Bid to Lower Treatment Cost". Wall Street Journal.
- ^ USPDI. Thompson. 2005. pp. 2741–2.
- ^ "Viread Prescribing Guidelines" (PDF). U.S. Food and Drug Administration. March 2006. Archived from the original on 2007-09-30. Retrieved 2007-02-12.
- ^ Delahunty T, Bushman L, Robbins B, Fletcher CV (2009). "The simultaneous assay of tenofovir and emtricitabine in plasma using LC/MS/MS and isotopically labeled internal standards". J. Chrom. B 877 (20–21): 1907–1914. doi:10.1016/j.jchromb.2009.05.029.
- ^ Kearney BP, Yale K, Shah J, Zhong L, Flaherty JF (2006). "Pharmacokinetics and dosing recommendations of tenofovir disoproxil fumarate in hepatic or renal impairment". Clin. Pharmacokinet. 45 (11): 1115–24. doi:10.2165/00003088-200645110-00005. PMID 17048975.
- ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, California, 2008, pp. 1490–1492.
- ^ Okwundu CI, Uthman OA, Okoromah CAN (2012). "Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals". Cochrane Database Syst Rev (7): CD007189. doi:10.1002/14651858.CD007189.pub3. PMID 22786505.
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