Tenofovir disoproxil fumarate

Overview

Tenofovir disoproxil fumarate, a prodrug of tenofovir[Trade name: “Viread”] developed by Gilead Sciences, is a kind of nucleotide-analogues antiretroviral drugs, taking effect through acting as the reverse transcriptase inhibitors[nRTIs], which block reverse transcriptase, an enzyme crucial to viral production in HIV-infected people^[1-4]. It should be noted that it is the first nucleotide reverse transcriptase inhibitor that has ever used for the treatment of HIV infection^[5]. Tenofovir disoproxil fumarate is converted to tenofovir in vivo, which is an acyclic nucleoside phosphonate[nucleotide] analog of adenosine 5'-monophosphate^[5,6]. It is generally used in combination with other kinds of medicine. HIV medicines can't cure HIV/AIDS, but taking a combination of HIV medicines[called an HIV regimen] every day can help people with HIV live longer, healthier lives^[7]. Based on the FDA document, tenofovir disoproxil fumarate can also be for the treatment of chronic hepatitis B virus[HBV] infection in adults and children 12 years of age and older^{[1,3, 4, 8]}.

Indication and application

Tenofovir disoproxil fumarate[trade name: Viread®], an antiviral drug, is indicated as the treatment for both HIV and Hepatitis B virus[HBV]. Viread® 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. It is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older^[2,9].

Mode of action

Tenofovir[the prodrug type of Viread] can effectively inhibit the activity of HIV reverse transcriptase by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, leading to DNA chain termination^{[1, 5, 7, 8]}. Specifically, the drugs are analogues of the naturally occurring deoxynucleotides needed to synthesize the viral DNA and they compete with the natural deoxynucleotides for incorporation into the growing viral DNA chain^{[8, 10, 11]}. However, unlike the natural deoxynucleotides substrates, NRTIs and NTRTIs[nucleoside/tide reverse transcriptase inhibitors] lack a 3'-hydroxyl group on the deoxyribose moiety. As a result, following incorporation of an NRTI or an NtRTI, the next incoming deoxynucleotide cannot form the next 5'-3' phosphodiester bond needed to extend the DNA chain. Thus, when an NRTI or NtRTI is incorporated, viral DNA synthesis is halted, a process known as chain termination. All NRTIs and NtRTIs are classified as competitive substrate inhibitors^[2].

Adverse reactions

Common adverse reactions include back pain, headache, lack or loss of strength, pain, redness of the skin, skin rash as well as itching skin^[3]. Severe adverse reactions of Tenofovir disoproxil fumarate may include severe acute exacerbation of Hepatitis, new onset or worsening renal impairment, lactic acidosis/severe hepatomegaly with steatosis, bone effects and immune re-constitution syndrome and liver impairment^[3]. Some less common side effects include chest pain, cough, fever of chills, weight loss, joint pain and swelling, itching and crawling tightness in the chest and trouble in breathing. In rare cases, abdominal or stomach discomfort, decreased appetite, diarrhea, fast, shallow breathing, general feeling of discomfort, muscle pain or cramping, unusual tiredness or weakness could occur^{[4, 9]}.

Warning and precaution

Viread should not be taken together with adefovir[Hepsera], or with used in combination with medicines that contain tenofovir[Atripla, Biktarvy, Cimduo, Complera, Descovy, Genvoya, Odefsey, Stribild, Symfi, or Truvada]. If patients have ever had chronic hepatitis B, Viread can restore the condition or even worse it. In this case, frequent blood tests is required to check your liver function. Do not stop using tenofovir disoproxil without first talking to your healthcare providers. This medicine may cause a serious condition called lactic acidosis^{[1, 3, 4, 9]}.
Get emergency medical help if you have even mild symptoms such as: muscle pain or weakness, numb or cold feeling in your arms and legs, trouble breathing, stomach pain, nausea with vomiting, fast or uneven heart rate, dizziness, or feeling very weak or tired. Viread can also cause severe or life-threatening effects on your liver. Call your doctor at once if you have: nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice[yellowing of the skin or eyes]^{[3, 4, 9]}.
Children with HIV who are younger than 2 years old as well as children with hepatitis B who are younger than 12 years old should be disabled from using Viread^{[3, 9]}.
Patients who have liver diseases, kidney disease or with low bone mineral density should ask doctors for advice before taking Viread. It may be not that safe for Women during pregnant or lactation stage to take Viread, so consult doctors before using it^[3].
Bone mineral density monitoring should be considered in patients who have a history of pathologic bone fracture or at risk for osteopenia^[9].
Some more tips:
Avoid sharing needles or other injection equipment as well as personal items that can have blood or body fluids on them, liketoothbrushes and razor blades. Avoid having any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood. Avoid breastfeed since tenofovir is excreted in breast milk and it is not known whether it can harm the baby. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk^[9].
Viread may cause either lactic acidosis or severe liver problem. Ask the doctor for help immediately when you have the following symptoms: feeling weak or tired, unusual muscle pain, trouble breathing, stomach pain associated with nausea or vomiting, feeling dizzy or lightheaded, fast or irregular heartbeat or cold or blue hands or feet, yellowing skin and whiting eye, dark-colored unit, loss of appetite, nausea and light-colored bowel movement^[3,9].

References

1. Editor, Text. "New Antiretroviral for HIV Infection. approved by the FDA tenofovir disoproxil fumarate Viread." American Family Physician[2002].
2. https://www.drugbank.ca/drugs/DB00300
3. https://aidsinfo.nih.gov/drugs/290/tenofovir-disoproxil-fumarate/0/patient/
4. https://www.drugs.com/pro/viread.html
5. Coleman, C., J. Ross, and P. Reddy. "Tenofovir disoproxil fumarate: The first nucleotide reverse transcriptase inhibitor for treatment of patients with HIV-1 infection." Formulary[2002].
6. Cooper, R. D, et al. "Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. " Clinical Infectious Diseases 51.5(2010]:496-505.
7. Lysengwilliamson, K. A., N. A. Reynolds, and G. L. Plosker. "Tenofovir disoproxil fumarate: a review of its use in the management of HIV infection. " Drugs 65.8(2005]:413-432.
8. Heathcote, E. J., et al. "Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. " Gastroenterology140.1(2011]:132-143.
9. https://www.rxlist.com/viread-drug.htm#indications_dosage
10. Miller MD, Margot NA, Hertogs K, Larder B, Miller V: Antiviral activity of tenofovir[PMPA] against nucleoside-resistant clinical HIV samples. Nucleosides Nucleotides Nucleic Acids. 2001 Apr-Jul;20(4-7]:1025-8.
11. Buti, M, and M. Homs. "Tenofovir disoproxil fumarate in the treatment of chronic hepatitis B." Expert Rev Gastroenterol Hepatol 6.4(2012]:413-421.

Description

Tenofovir disoproxil is a prodrug of the acyclic nucleoside phosphonate, tenofovir . Tenofovir is converted by cellular enzymes to tenofovir diphosphate, an obligate chain terminator that inhibits the activity of HIV reverse transcriptase and hepatitis B virus polymerase. Due to its rapid intracellular uptake, the anti-HIV activity of tenofovir disoproxil is reportedly >100-fold greater than that of the negatively charged tenofovir in a T cell line and primary blood lymphocytes.

Description

Tenofovir disoproxil fumarate (tenofovir DF) is the first nucleotide analog reverse transcriptase inhibitor (NRTI) to be launched in the US as a new oral treatment for HIV infection. This inhibitor can be prepared in six steps from (S)-glycidol by successive hydrogenation and intramolecular esterification to give the cyclic carbonate which reacts with adenine to afford the key hydroxypropyl adenine. The latter is transformed into the phosphonic acid [(R)-PMPA] condensed with the appropriate carbonate to give the phosphonic acid diester. Tenofovir DF is a water soluble diester that acts as a prodrug which is rapidly hydrolyzed to form the free tenofovir (analog of adenosine monophosphate) that acts only after two intracollular phosphorylation steps as a potent competitive inhibitor for reverse transcriptase. Tenofovir as the triphosphate form is then incorporated into DNA and causes DNA chain termination. In contrast to nucleoside analogs, tenofovir does not require initial intracellular phosphorylation, a limiting factor in resting cells. Tenofovir DF diffuses rapidly into cells due to its liphophilicity, unlike tenofovir, which requires an endocytosis transport process. The in vitro anti HIV activity of the oral prodrug is substantially greater than that of tenofovir alone (up to 100-fold), related to more rapid/extensive cellular uptake. Despite the fact that the prodrug is rapidly converted to free tenofovir in plasma after oral absorption, it is suggested that even small amounts of prodrug can provide enhanced antMral activity. In clinical studies, tenofovir DF has been shown to reduce the level of HIV in the blood for up to 48 weeks when added to patient's existing antiretroviral regimens. The drug also reduced viral load even in patients whose HIV had developed resistance to currently available antiretroviral drugs. Tenofovir DF is unique in demonstrating efficacy against 3TC (lamivudine)-resistant HIV strains. Moreover, the long intracellular half-life (from 12 to 50h) of the tefonovir diphosphate allowing for once daily dosing is probably an important factor in the efficacy of this drug/n vivo. The drug is eliminated by the kidney, is not metabolized by the liver and is not associated with P450 interactions. The bioavailability of the prodrug was increased significantly when taken with food from 27 to 40%. The oral bioavailabilty of tenofovir is < 10%.

Chemical Properties

White Solid

Originator

Gilead Sciences (US)

Uses

Acyclic phosphonate nucleotide analogue; reverse transcriptase inhibitor. Used as an anti-HIV agent. Antiviral.

Uses

An acyclic phosphonate nucleotide analog and selective HIV-1 RT inhibitor

Uses

tyrosinase inhibitor used for skin lightening and anti-melasma

Definition

ChEBI: A fumarate salt prepared from equimolar amounts of tenofovir disoproxil and fumaric acid. It is used in combination therapy for the treatment of HIV infection.

brand name

Viread (Gilead Sciences).

General Description

Pharmaceutical secondary standards for application in quality control provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards

Biochem/physiol Actions

Tenofovir disoproxil fumarate is a prodrug of tenofovir, a nucleotide analogue reverse transcriptase inhibitor (nRTI) that causes premature termination of DNA transcription. In a T cell line and primary blood lymphocytes, the antiviral activity of tenofovir disoproxil was shown to be more than 100-fold greater than tenofovir because of its rapid intracellular uptake. Tenofovir disoproxil fumarate has been used alone and in various combinations for the prevention and treatment of HIV/AIDS and chronic hepatitis B infections and is on the World Health Organization′s List of Essential Medicines.

Synthesis

Synthesis of (R)-(((((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphono)bis(oxy)bis(methylene)diisopropyl dicarbonate fumarate from isopropyl chloromethyl carbonate, fumaric acid and (R)-((1-(6-amino-9H-purin-9-yl)propan-2-yl)oxy)methyl)phosphono)bis(oxy)bis(methylene)diisopropyl dicarbonate fumarate in general The steps were as follows: in a reactor, 4.0 g of tenofovir (PMPA), 15 mL of N-methylpyrrolidone and 5.8 mL of triethylamine were added. the reaction mixture was heated to 63 °C and stirred for 30 minutes, followed by the addition of 10 g of chloromethyl isopropyl dicarbonate, and the stirring was continued by maintaining this temperature for 4 hours. Upon completion of the reaction, the mixture was cooled to room temperature, further cooled to 5 °C and 25 mL of distilled water pre-cooled to below 15 °C was slowly added. after stirring at 15 °C for 1 h, the mixture was extracted twice with dichloromethane 15 mL. The organic layers were combined and washed twice with 10 mL of distilled water and subsequently dried with magnesium sulfate. After filtration, the organic layer was concentrated under reduced pressure to give tenofovir desoproxil (TD) oily form. The TD oily form was dissolved in 35 mL of isopropanol, 1.6 g of fumaric acid was added, and the temperature was raised to 50°C with stirring until complete dissolution. This was followed by slow cooling to 25°C and further cooling to 3°C, maintaining this temperature with stirring for 4 hours. The precipitated crystals were filtered, washed with isopropanol and dried under vacuum at 40 °C to obtain tenofovir disoproxil fumarate (TDF) 4.7 g in 53% yield. The resulting TDF 4.7g was dissolved in isopropanol 40mL and heated to 50°C with stirring until completely dissolved. Slowly cooled to 25°C, then to 3°C and kept at this temperature with stirring for 4 hours. The crystals were filtered, washed with isopropanol and dried under vacuum at 40 °C to give a final TDF crystalline form of 4.3 g in 90% yield.

References

[1] fung hb, stone ea, piacenti fj. tenofovir disoproxil fumarate: a nucleotide reverse transcriptase inhibitor for the treatment of hiv infection. clin ther. 2002 oct;24(10):1515-48.
[2] brian p. kearney, john f. flaherty, jaymin shah. tenofovir disoproxil fumarate. clinical pharmacokinetics. august 2004, volume 43, issue 9, pp 595-612