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| Pronunciation | /ˌtəˈnoʊfəvɪərˌdɪsəˈprɑːksəl/ |
| Trade names | Viread, others |
| Other names | Bis(POC)PMPA |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a602018 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | 25% |
| Metabolism | Ester hydrolysis |
| Metabolites | Tenofovir |
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| ECHA InfoCard | 100.129.993 |
| Chemical and physical data | |
| Formula | C19H30N5O10P |
| Molar mass | 519.448 g·mol−1 |
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| Other names | 9-(2-Phosphonyl-methoxypropyly)adenine (PMPA) |
| MedlinePlus | a602018 |
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| Protein binding | < 1% |
| Metabolism | Phosphorylation |
| Metabolites | Tenofovir diphosphate (active metabolite) |
| Eliminationhalf-life | 17 hours |
| Excretion | Kidney |
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| ECHA InfoCard | 100.129.993 |
| Chemical and physical data | |
| Formula | C9H14N5O4P |
| Molar mass | 287.216 g·mol−1 |
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Tenofovir disoproxil, sold under the brand nameViread among others, is a medication used to treat chronichepatitis B and to prevent and treatHIV/AIDS.[3] It is generally recommended for use with other antiretrovirals.[3] It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after aneedlestick injury or other potential exposure.[3] It is sold both by itself and together in combinations such asemtricitabine/tenofovir,efavirenz/emtricitabine/tenofovir,[3] andelvitegravir/cobicistat/emtricitabine/tenofovir.[4] It does not cure HIV/AIDS or hepatitis B.[3][5] It is available by mouth as a tablet or powder.[3]
Common side effects include nausea, rash, diarrhea, headache, pain, depression, and weakness.[3] Severe side effects includehigh blood lactate and anenlarged liver.[3] There are no absolute contraindications.[3] It is often recommended duringpregnancy and appears to be safe.[3] It is anucleotide reverse transcriptase inhibitor and works by decreasing the ability of the viruses to replicate.[3]
Tenofovir was patented in 1996 and approved for use in the United States in 2001.[6] It is on theWorld Health Organization's List of Essential Medicines.[7] It is available in the United States as ageneric medication as of 2017.[8]
Tenofovir disoproxil is used for HIV-1 infection and chronic hepatitis B treatment. For HIV-1 infection, tenofovir is indicated in combination with other antiretroviral agents for people 2 years of age and older. For chronic hepatitis B patients, tenofovir is indicated for patients 12 years of age and older.[9]
Tenofovir can be used for HIV prevention in people who are at high risk for infection through sexual transmission or injecting drug use. ACochrane review examined the use of tenofovir for prevention of HIVbefore exposure and found that both tenofovir alone and thetenofovir/emtricitabine combination decreased the risk of contracting HIV for high risk patients.[10] The U.S.Centers for Disease Control and Prevention (CDC) also conducted a study in partnership with theThailand Ministry of Public Health to ascertain the effectiveness of providing people who inject drugs illicitly with daily doses of tenofovir as aprevention measure. The results revealed a 48.9% reduced incidence of the virus among the group of subjects who received the drug in comparison to the control group who received aplacebo.[11]
Tenofovir disoproxil is generally well tolerated with low discontinuation rates among the HIV and chronic hepatitis B population.[12] There are no contraindications for use of this drug.[9] The most commonly reported side effects due to use of tenofovir disoproxil were dizziness, nausea, and diarrhea.[12] Other adverse effects include depression, sleep disturbances, headache, itching, rash, and fever. The USboxed warning cautions potential onset oflactic acidosis or liver damage due to use of tenofovir disoproxil.[13]
Long term use of tenofovir disoproxil is associated withnephrotoxicity and bone loss. Presentation of nephrotoxicity can appear asFanconi syndrome, acute kidney injury, or decline ofglomerular filtration rate (GFR).[14] Discontinuation of tenofovir disoproxil can potentially lead to reversal of renal impairment. Nephrotoxicity may be due to proximal tubules accumulation of Tenofovir disoproxil leading to elevated serum concentrations.[12]
Tenofovir interacts withdidanosine and HIV-1 protease inhibitors. Tenofovir increases didanosine concentrations and can result in adverse effects such aspancreatitis andneuropathy. Tenofovir also interacts with HIV-1 protease inhibitors such asatazanavir, by decreasing atazanavir concentrations while increasing tenofovir concentrations.[9] In addition, since tenofovir is excreted by the kidney, medications that impair renal function can also cause problems.[15]
Tenofovir disoproxil is anucleotide analog reverse-transcriptase inhibitor (NtRTI).[16] It selectively inhibits viralreverse transcriptase, a crucial enzyme in retroviruses such ashuman immunodeficiency virus (HIV), while showing limited inhibition of human enzymes, such asDNA polymerases α, β, andmitochondrial DNA polymerase γ.[9][16] In vivo tenofovir disoproxil fumarate is converted to tenofovir, an acyclic analog of deoxyadenosine 5'-monophosphate (dAMP).Tenofovir lacks a hydroxyl group in the position corresponding to the 3' carbon of the dAMP, preventing the formation of the 5′ to 3′phosphodiester linkage essential for DNA chain elongation.[16] Once incorporated into a growing DNA strand, tenofovir causes premature termination of DNA transcription, preventing viral replication.[16]
Tenofovir disoproxil is aprodrug that is quickly absorbed from the gut and cleaved to release tenofovir.[9] Inside cells, tenofovir isphosphorylated to tenofovir diphosphate (which is analogous to atriphosphate, as tenofovir itself already has onephosphonate residue), the active compound that inhibits reverse transcriptase via chain termination.[15][16]
In fasting persons,bioavailability is 25%, and highestblood plasma concentrations are reached after one hour.[16] When taken with fatty food, highest plasma concentrations are reached after two hours, and thearea under the curve is increased by 40%.[16] It is an inhibitor ofcytochrome P450 1A2.[17]
Tenofovir is mainly excreted via the kidneys, both byglomerular filtration and bytubular secretion using the transport proteinsOAT1,OAT3 andABCC4.[15]
Tenofovir may be measured in plasma by liquid chromatography. Such testing is useful for monitoring therapy and to prevent drug accumulation and toxicity in people with kidney or liver problems.[18][19][20]
Tenofovir is a derivative ofadenine and this was the chemical starting point for its first published synthesis[21] which was included in patents to the compound.[22] During drug development, attention switched to thephosphonateester derivative, tenofovir disoproxil, which was the subject of extensive process chemistry to provide a viable manufacturing route.
Adenine is first reacted with achiral version ofpropylene carbonate withRabsolute configuration, using sodium hydroxide asbase. Under these conditions, the reaction isregioselective, withalkylation occurring exclusively in theimidazole ring and at theless-hindered carbon of thedioxolane. In the second step, thehydroxyl group is reacted with a phosphonic acid derivative, usingtert-butyllithium as base to ensure selective O-alkylation, with the formation of anether bond. Tenofovir is formed when the diethyl phosphonate group is converted to its acid usingtrimethylsilyl chloride in the presence of sodium bromide, a further refinement of the original manufacturing route.[23][24][25] The synthesis of the alternative ester in tenofovir disoproxil is completed by alkylation with the appropriatechloromethyl ether derivative and this may be purified as itsfumarate salt.[23]
Tenofovir was initially synthesized byAntonín Holý at the Institute of Organic Chemistry and Biochemistry of theCzechoslovak Academy of Sciences inPrague. The patent filed in 1986 makes no mention of the potential use of the compound for the treatment of HIV infection but claims activity againstherpes simplex virus.[22]
In 1985, Erik De Clercq and Holý described the activity of PMPA against HIV in cell culture.[26] Shortly thereafter, a collaboration with the biotechnology companyGilead Sciences led to the investigation of PMPA's potential as a treatment for HIV infected patients. In 1997 researchers from Gilead and the University of California, San Francisco demonstrated that tenofovir exhibits anti-HIV effects in humans when dosed by subcutaneous injection.[27]
The initial form of tenofovir used in these studies had limited potential for widespread use because it poorly penetrated cells and was not absorbed when given by mouth. Gilead developed a pro-drug version of tenofovir, tenofovir disoproxil. This version of tenofovir is often referred to simply as "tenofovir". In this version of the drug, the two negative charges of the tenofovir phosphonic acid group are masked, thus enhancing oral absorption.
Tenofovir disoproxil was approved in the U.S. in 2001, for the treatment of HIV, and in 2008, for the treatment ofchronichepatitis B.[28][29]
Tenofovir disoproxil can be takenby mouth and is sold under the brand name Viread, among others.[30] Tenofovir disoproxil is apro-drug form of tenofovir phosphonate, which is liberated intracellularly and converted to tenofovir disphophate.[31] It is marketed byGilead Sciences (as thefumarate, abbreviated TDF).[32]
Tenofovir disoproxil is also available in pills which combine a number of antiviral drugs into a single dose. Well-known combinations includeAtripla (tenofovir disoproxil/emtricitabine/efavirenz),Complera (tenofovir disoproxil/emtricitabine/rilpivirine),Stribild (tenofovir disoproxil/emtricitabine/elvitegravir/cobicistat), andTruvada (tenofovir disoproxil/emtricitabine).[30]
Gilead has created a second pro-drug form of the active drug, tenofovir diphosphate, calledtenofovir alafenamide. It differs from tenofovir disoproxil due to its activation in thelymphoid cells. This allows the active metabolites to accumulate in those cells, leading to lower systemic exposure and potential toxicities.[12]
