Tenofovir disoproxil, sold under the trade name Viread among others, is a medication used to treat chronic
hepatitis B
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
and to prevent and treat
HIV/AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
.
[ It is generally recommended for use with other antiretrovirals.][ It may be used for prevention of HIV/AIDS among those at high risk before exposure, and after a ]needlestick injury
A needlestick injury is the penetration of the skin by a hypodermic needle or other sharp object that has been in contact with blood, tissue or other body fluids before the exposure. Even though the acute physiological effects of a needlestick i ...
or other potential exposure.[ It is sold both by itself and together in combinations such as ]emtricitabine/tenofovir
Emtricitabine/tenofovir, sold under the brand name Truvada among others, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains the antiretroviral medications emtricitabine and tenofovir disopro ...
, efavirenz/emtricitabine/tenofovir,[ and ]elvitegravir/cobicistat/emtricitabine/tenofovir
Elvitegravir/cobicistat/emtricitabine/tenofovir, sold under the brand name Stribild, also known as the Quad pill, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. Elvitegravir, emtricitabine and tenofovir diso ...
. It does not cure HIV/AIDS or hepatitis B.[ It is available by mouth as a tablet or powder.]
Common side effects include nausea, rash, diarrhea, headache, pain, depression, and weakness.[ Severe side effects include high blood lactate and an ]enlarged liver
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...
.[ There are no absolute contraindications.][ It is often recommended during ]pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
and appears to be safe.[ It is a ]nucleotide reverse transcriptase inhibitor
Reverse-transcriptase inhibitors (RTIs) are a class of antiretroviral drugs used to treat HIV infection or AIDS, and in some cases hepatitis B. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase that is required for replicati ...
and works by decreasing the ability of the viruses to replicate.[
Tenofovir was patented in 1996 and approved for use in the United States in 2001. It is on the ]World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. It is available in the United States as a generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
as of 2017.
Medical uses
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.[Gilead Sciences, Inc]
Prescribing Information.
Revised: November 2012.
HIV risk reduction
Tenofovir can be used for HIV prevention in people who are at high risk for infection through sexual transmission or injecting drug use. A Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health profes ...
examined the use of tenofovir for prevention of HIV before exposure and found that both tenofovir alone and the tenofovir/emtricitabine
Emtricitabine/tenofovir, sold under the brand name Truvada among others, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains the antiretroviral medications emtricitabine and tenofovir disoprox ...
combination decreased the risk of contracting HIV for high risk patients. The U.S. Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency, under the Department of Health and Human Services, and is headquartered in Atlanta, Georgi ...
(CDC) also conducted a study in partnership with the Thailand Ministry of Public Health to ascertain the effectiveness of providing people who inject drugs illicitly with daily doses of tenofovir as a prevention 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 a placebo
A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures.
In general ...
.
Adverse effects
Tenofovir disoproxil is generally well tolerated with low discontinuation rates among the HIV and chronic hepatitis B population. There are no contraindications for use of this drug. The most commonly reported side effects due to use of tenofovir disoproxil were dizziness, nausea, and diarrhea. Other adverse effects include depression, sleep disturbances, headache, itching, rash, and fever. The US boxed warning
In the United States, a boxed warning (sometimes "black box warning", colloquially) is a type of warning that appears on the package insert for certain prescription drugs, so called because
the U.S. Food and Drug Administration specifies that it ...
cautions potential onset of lactic acidosis
Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates d ...
or liver damage due to use of tenofovir disoproxil.
Long term use of tenofovir disoproxil is associated with nephrotoxicity Nephrotoxicity is toxicity in the kidneys. It is a poisonous effect of some substances, both toxic chemicals and medications, on kidney function. There are various forms, and some drugs may affect kidney function in more than one way. Nephrotoxin ...
and bone loss. Presentation of nephrotoxicity can appear as Fanconi syndrome
Fanconi syndrome or Fanconi's syndrome (, ) is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity (for example, from toxi ...
, acute kidney injury, or decline of glomerular filtration rate
Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood p ...
(GFR). 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.
Interactions
Tenofovir interacts with didanosine
Didanosine (ddI, DDI), sold under the brand name Videx, is a medication used to treat HIV/AIDS. It is used in combination with other medications as part of highly active antiretroviral therapy (HAART). It is of the reverse-transcriptase inhibitor ...
and HIV-1 protease inhibitors. Tenofovir increases didanosine concentrations and can result in adverse effects such as pancreatitis
Pancreatitis is a condition characterized by inflammation of the pancreas. The pancreas is a large organ behind the stomach that produces digestive enzymes and a number of hormones. There are two main types: acute pancreatitis, and chronic pancr ...
and neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...
. Tenofovir also interacts with HIV-1 protease inhibitors such as atazanavir
Atazanavir, sold under the brand name Reyataz among others, is an antiretroviral medication used to treat HIV/AIDS. It is generally recommended for use with other antiretrovirals. It may be used for prevention after a needlestick injury or other ...
, by decreasing atazanavir concentrations while increasing tenofovir concentrations. In addition, since tenofovir is excreted by the kidney, medications that impair renal function can also cause problems.
Pharmacology
Mechanism of action
Tenofovir disoproxil is a nucleotide analog reverse-transcriptase inhibitor (NtRTI). It selectively inhibits viral reverse transcriptase
A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by viruses such as HIV and hepatitis B to replicate their genomes, ...
, a crucial enzyme in retroviruses such as human immunodeficiency virus (HIV), while showing limited inhibition of human enzymes, such as DNA polymerase
A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create ...
s α, β, and mitochondrial DNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
polymerase γ.[Drugbank]
Tenofovir
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
In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups () in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage . Discussion of phosphodiesters is d ...
linkage essential for DNA chain elongation. Once incorporated into a growing DNA strand, tenofovir causes premature termination of DNA transcription, preventing viral replication.
Pharmacokinetics
Tenofovir disoproxil is a prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
that is quickly absorbed from the gut and cleaved to release tenofovir. Inside cells, tenofovir is phosphorylate
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, ...
d to tenofovir diphosphate (which is analogous to a ''tri''phosphate, as tenofovir itself already has one phosphonate
In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly ...
residue), the active compound that inhibits reverse transcriptase via chain termination.
In fasting persons, bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
is 25%, and highest blood plasma
Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...
concentrations are reached after one hour. When taken with fatty food, highest plasma concentrations are reached after two hours, and the area under the curve
In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...
is increased by 40%. It is an inhibitor of cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
1A2.
Tenofovir is mainly excreted via the kidneys, both by glomerular filtration
Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pre ...
and by tubular secretion
Renal physiology (Latin ''rēnēs'', "kidneys") is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, ...
using the transport proteins OAT1
The organic anion transporter 1 (OAT1) also known as solute carrier family 22 member 6 (SLC22A6) is a protein that in humans is encoded by the ''SLC22A6'' gene. It is a member of the organic anion transporter#Organic anion transporter (OAT) family ...
, OAT3
Solute carrier family 22 member 8, or organic anion transporter 3 (OAT3), is a protein that in humans is encoded by the ''SLC22A8'' gene.
Function
OAT3 is involved in the transport and excretion of organic ions some of which are drugs (e.g., p ...
and ABCC4
ATP-binding cassette sub-family C member 4 (ABCC4), also known as the multidrug resistance-associated protein 4 (MRP4) or multi-specific organic anion transporter B (MOAT-B), is a protein that in humans is encoded by the ''ABCC4'' gene.
ABCC4 act ...
.
Detection in body fluids
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.
Chemistry
Tenofovir is a derivative of adenine
Adenine () ( symbol A or Ade) is a nucleobase (a purine derivative). It is one of the four nucleobases in the nucleic acid of DNA that are represented by the letters G–C–A–T. The three others are guanine, cytosine and thymine. Its derivati ...
and this was the chemical starting point for its first published synthesis which was included in patents to the compound. During drug development, attention switched to the phosphonate
In organic chemistry, phosphonates or phosphonic acids are organophosphorus compounds containing groups (where R = alkyl, aryl, or just hydrogen). Phosphonic acids, typically handled as salts, are generally nonvolatile solids that are poorly ...
ester
In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ar ...
derivative, tenofovir disoproxil, which was the subject of extensive process chemistry to provide a viable manufacturing route.
:
Adenine is first reacted with a chiral
Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable from ...
version of propylene carbonate
Propylene carbonate (often abbreviated PC) is an organic compound with the formula C4H6O3. It is a cyclic carbonate ester derived from propylene glycol. This colorless and odorless liquid is useful as a polar, aprotic solvent. Propylene carbo ...
with ''R'' absolute configuration
Absolute configuration refers to the spatial arrangement of atoms within a chiral molecular entity (or group) and its resultant stereochemical description. Absolute configuration is typically relevant in organic molecules, where carbon is bonde ...
, using sodium hydroxide as base. Under these conditions, the reaction is regioselective
In chemistry, regioselectivity is the preference of chemical bonding or breaking in one direction over all other possible directions. It can often apply to which of many possible positions a reagent will affect, such as which proton a strong Base ( ...
, with alkylation
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effecting ...
occurring exclusively in the imidazole
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole Diazole refers ...
ring and at the less-hindered carbon of the dioxolane
Dioxolane is a heterocyclic acetal with the chemical formula (CH2)2O2CH2. It is related to tetrahydrofuran by interchange of one oxygen for a CH2 group. The corresponding saturated 6-membered C4O2 rings are called dioxanes. The isomeric 1,2-diox ...
. In the second step, the hydroxyl group is reacted with a phosphonic acid derivative, using ''tert''-butyllithium as base to ensure selective O-alkylation, with the formation of an ether
In organic chemistry, ethers are a class of compounds that contain an ether group—an oxygen atom connected to two alkyl or aryl groups. They have the general formula , where R and R′ represent the alkyl or aryl groups. Ethers can again be c ...
bond. Tenofovir is formed when the diethyl phosphonate group is converted to its acid using trimethylsilyl chloride
Trimethylsilyl chloride, also known as chlorotrimethylsilane is an organosilicon compound ( silyl halide), with the formula (CH3)3SiCl, often abbreviated Me3SiCl or TMSCl. It is a colourless volatile liquid that is stable in the absence of water. ...
in the presence of sodium bromide, a further refinement of the original manufacturing route. The synthesis of the alternative ester in tenofovir disoproxil is completed by alkylation with the appropriate chloromethyl ether derivative and this may be purified as its fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
salt.[
]
History
Tenofovir was initially synthesized by Antonín Holý
Antonín Holý (1 September 1936 – 16 July 2012) was a pioneering Czech scientist. He specialised in the field of chemistry and cooperated on the development of important antiretroviral drugs used in the treatment of HIV and hepatitis B. He ...
at the Institute of Organic Chemistry and Biochemistry of the Czechoslovak Academy of Sciences
The Czechoslovak Academy of Sciences (Czech: ''Československá akademie věd'', Slovak: ''Česko-slovenská akadémia vied'') was established in 1953 to be the scientific center for Czechoslovakia. It was succeeded by the Czech Academy of Science ...
in Prague
Prague ( ; cs, Praha ; german: Prag, ; la, Praga) is the capital and largest city in the Czech Republic, and the historical capital of Bohemia. On the Vltava river, Prague is home to about 1.3 million people. The city has a temperate ...
. The patent filed in 1986 makes no mention of the potential use of the compound for the treatment of HIV infection but claims activity against herpes simplex
Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected.
Oral herpes involves the face or mouth. It may result in small blisters in groups often called cold ...
virus.[
In 1985, De Clercq and Holý described the activity of PMPA against HIV in cell culture. Shortly thereafter, a collaboration with the biotechnology company ]Gilead Sciences
Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and C ...
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.
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 of chronic hepatitis B
Hepatitis B is an infectious disease caused by the ''Hepatitis B virus'' (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection.
Many people have no symptoms during an initial infection. Fo ...
.
Drug forms
Tenofovir disoproxil can be taken by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
and is sold under the brand name Viread, among others. Tenofovir disoproxil is a pro-drug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...
form of tenofovir phosphonate, which is liberated intracellularly and converted to tenofovir disphophate. It is marketed by Gilead Sciences
Gilead Sciences, Inc. () is an American biopharmaceutical company headquartered in Foster City, California, that focuses on researching and developing antiviral drugs used in the treatment of HIV/AIDS, hepatitis B, hepatitis C, influenza, and C ...
(as the fumarate
Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297.
The salts and esters are known as f ...
, abbreviated TDF).
Tenofovir disoproxil is also available in pills which combine a number of antiviral drugs into a single dose. Well-known combinations include Atripla
Efavirenz/emtricitabine/tenofovir, sold under the brand name Atripla among others, is a fixed-dose combination antiretroviral medication used to treat HIV/AIDS. It contains efavirenz, emtricitabine, and tenofovir disoproxil. It can be used by ...
(tenofovir disoproxil/emtricitabine/efavirenz), Complera (tenofovir disoproxil/emtricitabine/rilpivirine), Stribild
Elvitegravir/cobicistat/emtricitabine/tenofovir, sold under the brand name Stribild, also known as the Quad pill, is a fixed-dose combination antiretroviral medication for the treatment of HIV/AIDS. Elvitegravir, emtricitabine and tenofovir diso ...
(tenofovir disoproxil/emtricitabine/elvitegravir/cobicistat), and Truvada
Emtricitabine/tenofovir, sold under the brand name Truvada among others, is a fixed-dose combination antiretroviral medication used to treat and prevent HIV/AIDS. It contains the antiretroviral medications emtricitabine and tenofovir disoprox ...
(tenofovir disoproxil/emtricitabine).
Gilead has created a second pro-drug form of the active drug, tenofovir diphosphate, called tenofovir alafenamide
Tenofovir alafenamide, sold under the brand name Vemlidy, is a hepatitis B virus (HBV) nucleotide reverse transcriptase inhibitor medication for the treatment of chronic hepatitis B virus (HBV) infection in adults with compensated liver dise ...
. It differs from tenofovir disoproxil due to its activation in the lymphoid cells
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic adapti ...
. This allows the active metabolites to accumulate in those cells, leading to lower systemic exposure and potential toxicities.
References
External links
*
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