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Clinical data
Trade names	Crixivan
AHFS/Drugs.com	Monograph
MedlinePlus	a696028
License data	EU EMA: by INN US FDA: Indinavir
Routes of administration	Oral
ATC code	J05AE02 (WHO)
Pharmacokinetic data
Bioavailability	~65%
Protein binding	60%
Metabolism	Hepatic via CYP3A4
Elimination half-life	1.8 ± 0.4 hours
Identifiers
IUPAC name (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	150378-17-9 Y
PubChem CID	5362440
DrugBank	DB00224 Y
ChemSpider	4515036 Y
UNII	9MG78X43ZT
KEGG	C07051 Y
ChEBI	CHEBI:44032 Y
ChEMBL	ChEMBL540914 N
NIAID ChemDB	005824
PDB ligand	MK1 (PDBe, RCSB PDB)
Chemical and physical data
Formula	C36H47N5O4
Molar mass	613.79 g/mol g·mol−1
3D model (JSmol)	Interactive image
SMILES 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 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 Y Key:CBVCZFGXHXORBI-PXQQMZJSSA-N Y
NY (what is this?)  (verify)

Indinavir (IDV; trade name Crixivan, manufactured by Merck) is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV/AIDS. It is administered orally in combination with other antiviral drugs. 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.

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

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.

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.

Unfortunately, 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. Drug users must significantly increase their water intake due to indinavir's low solubility that can cause it to crystallize. It has restrictions on what sorts of food may be eaten concurrently for 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.

Chemistry

Indinavir prevents the protease 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 can't form. Then, HIV viruses can't reproduce, causing a decrease in the viral load.

The drug that was sold by Merck was indinaivr anhydrous. Indinavir anhydrous 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 purposes inhibiting the protease in the HIV virus.

Side effects

The most common side effects of indinavir include:

• Gastrointestinal disturbances (abdominal pain, diarrhea, nausea, vomiting)
• General malaise and fatigue
• Nephrolithiasis/urolithiasis (the formation of kidney stones), which sometimes may lead to more severe condition including kidney failure
• Metabolic alterations including hyperlipidemia (cholesterol or triglyceride elevations) and hyperglycemia
• Alterations in body shape (lipodystrophy), colloquially known as "Crix belly"
• Increased levels of Bilirubin, causing skin and white parts of the eyes to turn yellow

Indinavir inhibits urinary nitrous oxide production and may inhibit nitric oxide production. Treatment with this drug is frequently associated with renal abnormalities, sterile leukocyturia, and reduced creatinine clearance.

Indinavir impairs endothelial function in healthy HIV-negative men and may accelerate atherosclerotic disease.

History

December, 1986: Merck's President, Dr. Edward Scolnick, announced that they would start a comprehensive AIDS research program. They started a laboratory dedicated to AIDS research in West Point, Pennsylvania. They placed Dr. Emilio Emini in charge of the laboratory.

January, 1987: The team of researchers comprised of Dr. Emini, Joel Huff, and Irving Sigal, kickstarted their studies by basing their project off of earlier research on the protease enzyme, renin.

File:Indinavir label.jpeg

FDA label of Indinavir sold under Merck

July, 1988: Dr. Nancy Kohl, Emilio Emini, et al, published in the Proceedings of the National Academy of the Science about the idea of inhibiting the protease.

February, 1989: Dr. Manuela Navia, Paula Fitzgerald, et al, published a paper which showed the three-dimensional structure of HIV's protease enzyme. This helped determine the future trajectory of the development of the inhibitor.

March, 1990: Researchers under Dr. Reider got 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.

March, 1991: Merck made decided to formulate a community advisory board comprised of AIDS activists who would help with the development effort of the drug. This was an unusual move because most pharmaceutical companies at this time would try to distance themselves from these activists in fear of backlash. Despite these efforts, they still faced serious backlash when they started to distribute their drugs due to the pricing and limited quantities.

January, 1992: Researchers synthesized indinavir sulfate (Crixivan), which was assigned compound number L-735,524.

July, 1992: They started to test L-735,524 on animals. They found out that it was safe for animals.

September, 1992: The company decided that it was safe to start human trials.

March, 1995: The company starts building facilities to start manufacturing the drug.

March 14, 1996: The Food and Drug Administration (FDA) approved indinavir, making it the eighth antiretroviral drug approved. It was first given its blessing by the FDA on March 1st 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. However, 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.

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.

Clinical Trials

In January of 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.

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 receieved 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.

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.

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 of development of opportunistic infections.

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. Therefore, this proves that a three-drug treatment is more efficient than a two-drug one.

Controversy

Supply

This became the biggest issue for many people who needed the drug. Due to the fact that indinavir got approved very quickly, Merck didn't 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 yet 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 are selling in such limited quantities.

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 spiked up and limited the number of people who could have access to this possibly life-saving drug.

Price

Despite the fact that indinavir costed 24% less than Invirase and 33% less than Norvir, it still costed about $12 for a daily dose. 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 costed a lot to research and develop the drug, and they didn't have enough supplies to sell it through a normal distributor system. Activists still protested against this price because it made it harder for people of lower socioeconomic statuses to have access to the drug.

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.