Indinavir

Last updated
Indinavir
Indinavir structure.svg
Indinavir ball-and-stick.png
Clinical data
Trade names Crixivan
AHFS/Drugs.com Monograph
MedlinePlus a696028
License data
Routes of
administration 		Oral
ATC code
Pharmacokinetic data
Bioavailability ~65%
Protein binding 60%
Metabolism Hepatic via CYP3A4
Elimination half-life 1.8 ± 0.4 hours
Identifiers
  • (2S)-1-[(2S,4R)-4-benzyl-2-hydroxy-4-{[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]carbamoyl}butyl]-N-tert-butyl-4-(pyridin-3-ylmethyl)piperazine-2-carboxamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
Formula C36H47N5O4
Molar mass 613.803 g·mol−1
3D model (JSmol)
  • CC(C)(C)NC(=O)[C@@H]1CN(CCN1C[C@H](C[C@@H](Cc2ccccc2)C(=O)N[C@H]3c4ccccc4C[C@H]3O)O)Cc5cccnc5
  • InChI=1S/C36H47N5O4/c1-36(2,3)39-35(45)31-24-40(22-26-12-9-15-37-21-26)16-17-41(31)23-29(42)19-28(18-25-10-5-4-6-11-25)34(44)38-33-30-14-8-7-13-27(30)20-32(33)43/h4-15,21,28-29,31-33,42-43H,16-20,22-24H2,1-3H3,(H,38,44)(H,39,45)/t28-,29+,31+,32-,33+/m1/s1 Yes check.svgY
  • Key:CBVCZFGXHXORBI-PXQQMZJSSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Indinavir (IDV; trade name Crixivan, made by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. Consequently, HIV viruses cannot reproduce, causing a decrease in the viral load. Commercially sold indinavir is indinavir anhydrous, which is indinavir with an additional amine in the hydroxyethylene backbone. This enhances its solubility and oral bioavailability, making it easier for users to intake. It was synthetically produced for the purpose of inhibiting the protease in the HIV virus. [1]

Contents

Currently, it is not recommended for use in HIV/AIDS treatment due to its side effects. Furthermore, it is controversial for many reasons starting from its development to its usage.

It was patented in 1991 and approved for medical use in 1996. [2]

Medical uses

Indinavir does not cure HIV/AIDS, but it can extend the length of a person's life for several years by slowing the progression of the disease. The type that is widely used and created by Merck is indinavir sulfate. The pills are created from sulfate salts and are sold in dosages of 100, 200, 333, and 400 mg of indinavir. It is normally used as one of the three drugs in a triple-combination therapy for the HIV virus. [1]

Commercially available capsules should be stored at 15 - 30 °C. It should be kept in a tight container so that it is kept away from moisture. Therefore, it is advised that users should keep the pills in the manufacturer-provided bottle and do not remove the desiccant. [1]

HIV-1 protease in complex with indinavir. PDB entry 2avo 2avo Indinavir.png
HIV-1 protease in complex with indinavir. PDB entry 2avo

Indinavir wears off quickly after dosing. Unboosted indinavir requires a very precise dosing of 400 mg every eight hours to thwart HIV from forming drug-resistant mutations, including resistances to other protease inhibitors. Boosted indinavir requires two 400-mg indinavir capsules with 1 to 2 100-mg ritonavir capsules twice a day. In both cases, the drugs must be taken with plenty of water one or two hours after a meal. It is recommended that users drink at least 1.5 liters a day when intaking the drug. Drug users must significantly increase their water intake due to indinavir's low solubility that can cause it to crystallize. There are restrictions on what sorts of food may be eaten concurrently with the unboosted indinavir treatment. Furthermore, it is no longer recommended to use in the United States for initial treatments due to pill burden and risk of kidney stones. [4]

Viral resistance

Many people were skeptical of being too hopeful with indinavir due to previous events that occurred with AZT. Viral resistance to the drug leads to the drug becoming useless since the virus evolves to have cells that are able to resist the protease inhibitor. In order to avoid this as much as possible, it is important for users to consistently take the exact amount of the drug at the allocated times. This fear of viral resistance caused a lot of users to be wary of the drug. [5]

Side effects

The most common side effects of indinavir include:

Chemical properties

Structure of protease and indinavir HIV protease-indinavir complex.jpg
Structure of protease and indinavir

Indinavir is a white crystalline powder. It is very soluble in water and methanol. Each capsule contains sulfate salt in addition to anhydrous lactose and magnesium stearate. The capsule shell is made of gelatin and titanium dioxide. Its melting point or its temperature of decomposition is 150 - 153 °C at which it starts to emit toxic vapors such as nitrogen oxides and sulfur oxides.

[4]

The drug fits inside the protease, stopping it from functioning normally. As a result, structural proteins, resulting from polypeptide products of gag and gag-pol genes, that are necessary for the HIV virions cannot form. Eventually, the viral load decreases because of the lack of reproduction. [1]

History

The official start to its development started in December 1986 when Merck's president, Edward Scolnick, announced that they would start a comprehensive AIDS research program. They started a laboratory dedicated to AIDS research in West Point, Pennsylvania and placed Emilio Emini in charge of the laboratory. [11] A couple months later on January, 1987, a team of researchers consisting of Emilio Emini, Joel Huff, and Irving Sigal, kickstarted their studies by basing their project off of earlier research on the protease enzyme, renin. [5] They were the ones who started the process of research and development into protease inhibitors and its relation to the virus. Over a year later, in July 1988, Nancy Kohl, Emilio Emini, et al., published in the Proceedings of the National Academy of the Science about the idea of inhibiting the protease. [11] On February, 1989, Manuela Navia, Paula Fitzgerald, et al., published a paper that showed the three-dimensional structure of HIV's protease enzyme. [5] Other researchers claim that this study helped determine the future trajectory of the development of the inhibitor. After much research, in March, 1990, researchers under Reider received a patent to synthesize part of L-689, 502 compound. These were similar to existing inhibitors. However, it failed safety assessments because of its toxicity. [11]

Seeing that the research on their drug was heading in the direction of eventually getting it on the market, Merck decided to formulate a community advisory board composed of AIDS activists who would help with the development effort of the drug in March 1991.[ citation needed ] Later on, Merck faced serious backlash from community members who though did not like the pricing and distribution of the drug.[ citation needed ]

In January 1992, researchers synthesized indinavir sulfate (Crixivan), which was assigned compound number L-735,524. They started to test L-735,524 on animals a couple months later and found that it was safe for animals. Consequently, the company decided that it was safe to start human trials on September of the same year. [11]

The Food and Drug Administration (FDA) approved indinavir on March, 1996, making it the eighth antiretroviral drug approved. It was first given its blessing by the FDA on March 1 then approved merely 42 days after the company filed the drug to the FDA. A major reason for this fast approval was the presentation Merck gave to the committee with results from Study 035 (see below). The fact that they had fast approval ran into trouble with groups like Treatment Action Group who thought that accelerated drug approval was not beneficial for people infected with HIV/AIDS. [5]

From then on, indinavir used with dual NRTIs set a new standard for treatment of HIV/AIDS. Protease inhibitors changed the nature of AIDS from a terminal illness to a somewhat manageable one. It significantly increased life expectancies and decreased noticeable symptoms from infectious diseases that were the result of a weakened immune system from the virus. Currently, it is being replaced by newer drugs that are more convenient to take, less likely to promote virus resistance, and less toxic, such as darunavir or atazanavir. [5]

Clinical trials

In January 1996, Merck & Co. proved that indinavir was a clinically efficient drug based on data from human trials. They were able to show that indinavir, when used with two other anti-HIV drugs, could significantly reduce the HIV viral load. [5]

Study 035

The study's goal was to show the different effects of different antiviral treatments. 97 patients were randomly assigned to one of the three groups: indinavir monotherapy, AZT and lamivudine, or all three agents. Eligible patients were those who received AZT for at least 6 months and have CD4 cell counts between 50 and 400, viral loads of at least 200,000 copies/mL, and had no prior antiretroviral therapy with protease inhibitor or lamivudine. [12]

The results of the study showed that the most effective treatment was the three drug treatment. After 24 weeks of treatment, 24 patients of the 28 patients who were treated with the three drugs were able to have viral load levels have less than 500 copies/ml. 12 out of 28 patients under indinavir monotherapy reached 500 copies/ml, and none of the thirty patients in AZT and lamivudine group got below 500 copies. [12]

ACTG 320

This study took a look at clinical efficiency of the different treatments. Patients had to have CD4 cell counts less than 200 and at least 3 months of AZT therapy before the trials. 1156 patients with a mean of 87 CD4 cell counts and mean viral load of 100,000 copies/ml were randomized to one of the two groups: AZT plus lamivudine or AZT plus lamivudine plus indinavir. Just like Study 035, patients couldn't be in the study if they had prior protease inhibitor treatment or lamivudine for more than one week. The end point of the study was death or development of opportunistic infections. [13]

After 38 weeks, 6% of the people in the three-drug group died while 11% of the people died in the two-drug group. There were higher CD4 cell counts and less viral load in patients assigned to the three-drug group, proving that a three-drug treatment is more efficient than a two-drug one. [13]

Controversy

Supply

Merck did not have enough time to prepare enough drugs to distribute for all those who were infected. 650,000 to 900,000 people were infected with the virus, and Merck could only provide drugs for about 25,000 to 30,000 people. Furthermore, the drug has to be taken consistently or else users face dangers, meaning that the company has to take into account refills for users who take the drugs. This situation of limited supply caused a lot of activists to be angry at the fact that they were selling in such limited quantities. [14]

Distribution

Because of its limited supply, Merck decided to adopt a single distributor system in which they would send indinavir to only one pharmaceutical retail company. They sold it to Stadtalnder's Pharmacy and limited quantities to Veteran Administration's hospitals and some managed-care organizations. This caused prices to be raised and limited the number of people who could have access to this possibly life-saving drug. [15]

Price

Indinavir cost about $12 for a daily dose, which is 24% less than Invirase and 33% less than Norvir. [14] Because the company used a single distributor system to sell their drugs, the retail price was marked up 37% by the pharmacy that sold it. In response to this hefty price, Merck stated that it cost a lot to research and develop the drug, and they did not have enough supplies to sell it through a normal distributor system. Activists protested against this price because it made it harder for people to have access to the drug. [15]

Related Research Articles

<span class="mw-page-title-main">Zidovudine</span> Antiretroviral medication

Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs as a strategy to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same-sex and opposite-sex partners so long as the HIV-positive partner maintains an undetectable viral load.

The spread of HIV/AIDS has affected millions of people worldwide; AIDS is considered a pandemic. The World Health Organization (WHO) estimated that in 2016 there were 36.7 million people worldwide living with HIV/AIDS, with 1.8 million new HIV infections per year and 1 million deaths due to AIDS. Misconceptions about HIV and AIDS arise from several different sources, from simple ignorance and misunderstandings about scientific knowledge regarding HIV infections and the cause of AIDS to misinformation propagated by individuals and groups with ideological stances that deny a causative relationship between HIV infection and the development of AIDS. Below is a list and explanations of some common misconceptions and their rebuttals.

Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS, hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

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 replication of HIV and other retroviruses.

<span class="mw-page-title-main">Zalcitabine</span> Chemical compound

Zalcitabine, also called dideoxycytidine, is a nucleoside analog reverse-transcriptase inhibitor (NRTI) sold under the trade name Hivid. Zalcitabine was the third antiretroviral to be approved by the Food and Drug Administration (FDA) for the treatment of HIV/AIDS. It is used as part of a combination regimen.

<span class="mw-page-title-main">Lamivudine</span> Chemical compound

Lamivudine, commonly called 3TC, is an antiretroviral medication used to prevent and treat HIV/AIDS. It is also used to treat chronic hepatitis B when other options are not possible. It is effective against both HIV-1 and HIV-2. It is typically used in combination with other antiretrovirals such as zidovudine, dolutegravir, and abacavir. Lamivudine may be included as part of post-exposure prevention in those who have been potentially exposed to HIV. Lamivudine is taken by mouth as a liquid or tablet.

<span class="mw-page-title-main">Atazanavir</span> Chemical compound

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 potential exposure. It is taken by mouth.

<span class="mw-page-title-main">Nevirapine</span> Chemical compound

Nevirapine (NVP), sold under the brand name Viramune among others, is a medication used to treat and prevent HIV/AIDS, specifically HIV-1. It is generally recommended for use with other antiretroviral medications. It may be used to prevent mother to child spread during birth but is not recommended following other exposures. It is taken by mouth.

<span class="mw-page-title-main">Saquinavir</span> Chemical compound

Saquinavir, sold under the brand name Invirase among others, is an antiretroviral medication used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect. It is taken by mouth.

<span class="mw-page-title-main">Raltegravir</span> Chemical compound

Raltegravir, sold under the brand name Isentress, is an antiretroviral medication used, together with other medication, to treat HIV/AIDS. It may also be used, as part of post exposure prophylaxis, to prevent HIV infection following potential exposure. It is taken by mouth.

Many major physiological processes depend on regulation of proteolytic enzyme activity and there can be dramatic consequences when equilibrium between an enzyme and its substrates is disturbed. In this prospective, the discovery of small-molecule ligands, like protease inhibitors, that can modulate catalytic activities has an enormous therapeutic effect. Hence, inhibition of the HIV protease is one of the most important approaches for the therapeutic intervention in HIV infection and their development is regarded as major success of structure-based drug design. They are highly effective against HIV and have, since the 1990s, been a key component of anti-retroviral therapies for HIV/AIDS.

Discovery and development of nucleoside and nucleotide reverse-transcriptase inhibitors began in the 1980s when the AIDS epidemic hit Western societies. NRTIs inhibit the reverse transcriptase (RT), an enzyme that controls the replication of the genetic material of the human immunodeficiency virus (HIV). The first NRTI was zidovudine, approved by the U.S. Food and Drug Administration (FDA) in 1987, which was the first step towards treatment of HIV. Six NRTI agents and one NtRTI have followed. The NRTIs and the NtRTI are analogues of endogenous 2´-deoxy-nucleoside and nucleotide. Drug-resistant viruses are an inevitable consequence of prolonged exposure of HIV-1 to anti-HIV drugs.

The Berlin patient is an anonymous person from Berlin, Germany, who was described in 1998 as exhibiting prolonged "post-treatment control" of HIV viral load after HIV treatments were interrupted.

<span class="mw-page-title-main">Jacques Leibowitch</span> French physician and researcher (1942–2020)

Jacques Leibowitch was a French medical doctor and clinical researcher known for his contributions to the knowledge and treatment of HIV and AIDS, starting with his initial designation of a human retrovirus as the cause of AIDS, and his ground-breaking use of triple combination therapy for the effective control of HIV in the patient. A practicing physician in the infectiology department of the Raymond Poincaré University Hospital of Garches, University lecturer Emeritus, he led the treatment program ICCARRE that proposes a dramatic reduction of weekly anti-HIV drug intake, down to 2-3 anti-viral pills a day taken 2 to 3 or 4 days a week, as opposed to the presently recommended seven days a week, as still universally prescribed. These reduced medical dosages are adequate, necessary and sufficient according to the results of his exploratory clinical research carried out since 2003. He is the author of the books "Un virus étrange venu d'ailleurs", and "Pour en finir avec le sida".

<span class="mw-page-title-main">VIR-576</span>

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<span class="mw-page-title-main">Abacavir/dolutegravir/lamivudine</span> Drug combination for HIV

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References

  1. 1 2 3 4 "Indinavir". PubChem. U.S. National Library of Medicine. Retrieved 2018-10-22.
  2. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 509. ISBN   9783527607495.
  3. ↑ Liu F, Boross PI, Wang YF, Tozser J, Louis JM, Harrison RW, Weber IT (December 2005). "Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S". Journal of Molecular Biology. 354 (4): 789–800. doi:10.1016/j.jmb.2005.09.095. PMC   1403828 . PMID   16277992.
  4. 1 2 3 4 "Crixivan (Indinavir Sulfate): Side Effects, Interactions, Warning, Dosage & Uses". RxList. Retrieved 2018-11-08.
  5. 1 2 3 4 5 6 Cohen J (June 1996). "Protease inhibitors: a tale of two companies". Science. 272 (5270): 1882–1883. Bibcode:1996Sci...272.1882C. doi:10.1126/science.272.5270.1882. PMID   8658156. S2CID   84869965.
  6. ↑ Capaldini L (August 1997). "Protease inhibitors' metabolic side effects: cholesterol, triglycerides, blood sugar, and "Crix belly." Interview with Lisa Capaldini, M.D. Interview by John S. James". AIDS Treatment News (277): 1–4. PMID   11364559.
  7. ↑ "Indinavir". livertox.nih.gov. Retrieved 2018-10-21.
  8. ↑ MacGill M (July 24, 2018). "High bilirubin levels: Meaning, symptoms, and tests". Medical News Today. Retrieved 2018-10-21.
  9. ↑ Eira M, Araujo M, Seguro AC (August 2006). "Urinary NO3 excretion and renal failure in indinavir-treated patients". Brazilian Journal of Medical and Biological Research = Revista Brasileira de Pesquisas Medicas e Biologicas. 39 (8): 1065–1070. doi: 10.1590/s0100-879x2006000800009 . PMID   16906281.
  10. ↑ Shankar SS, Dubé MP, Gorski JC, Klaunig JE, Steinberg HO (November 2005). "Indinavir impairs endothelial function in healthy HIV-negative men". American Heart Journal. 150 (5): 933.e1–933.e7. doi:10.1016/j.ahj.2005.06.005. PMID   16290967.
  11. 1 2 3 4 "History and the Discovery and Development of Crixivan". quod.lib.umich.edu. Retrieved 2018-10-24.
  12. 1 2 Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, et al. (September 1997). "Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy". The New England Journal of Medicine. 337 (11): 734–739. doi: 10.1056/nejm199709113371102 . PMID   9287228.
  13. 1 2 Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, et al. (September 1997). "A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team". The New England Journal of Medicine. 337 (11): 725–733. doi: 10.1056/nejm199709113371101 . PMID   9287227. S2CID   24043435.
  14. 1 2 Tanouye E, Waldholz M (7 May 1996). "Merck Attracts Controversy With Marketing of AIDS Drug". Wall Street Journal. Retrieved 2018-11-08.
  15. 1 2 Hilts PJ (15 March 1996). "With Record Speed, F.D.A. Approves a New AIDS Drug". The New York Times. Retrieved 2018-10-24.
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