Nelfinavir
Encyclopedia
Nelfinavir is an antiretroviral drug
used in the treatment of the human immunodeficiency virus (HIV). Nelfinavir belongs to the class of drugs known as protease inhibitors
(PIs) and like other PIs is generally used in combination with other antiretroviral drugs.
Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease
inhibitor (Ki=2nM) and is being widely prescribed in combination with HIV
reverse transcriptase inhibitors for the treatment of HIV infection.
.
The U.S. Food and Drug Administration (FDA) approved it for therapeutic use on March 14, 1997, making it the twelfth approved antiretroviral. The initial product launched proved to be the largest "biotech launch" in the history of the pharmaceutical industry achieving first full year sales exceeding $335M US. Agouron's patent
on the drug will expire in 2014.
On the 6 June 2007, both the Medicines and Healthcare products Regulatory Agency
and the European Medicines Agency
put out an alert requesting the recall of any of the drug in circulation because of fears that batches of the therapy may have been contaminated with potentially cancer-causing chemicals
as a side effect.
: it inhibits HIV-1
and HIV-2 proteases. This protease is an enzyme which cleaves viral protein molecules into smaller fragments, and it is vital for both the replication of the virus within the cell and also the release of mature viral particles from an infected cell. Though this mode of action is common to all protease inhibitors, the precise mode of binding of nelfinavir to the enzyme may be sufficiently unique to reduce cross-resistance between it and other PIs. Also, not all PIs inhibit both HIV-1 and HIV-2 proteases.
or abdominal pain. Infrequent (experienced by one in one thousand to one in one hundred patients; 0.01 - 0.1%) adverse effects are fatigue, urination, rash
, mouth ulcer
s or hepatitis
. Rarely (less than one in one thousand patients; under 0.01%) nephrolithiasis, arthralgia
, Leukopenia
, pancreatitis
or allergic
reactions may occur.
), it is able to inhibit the growth of a variety of different cancer types and triggers cell death (apoptosis
).
When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals. In vitro tests showed it may work well with sorafenib
In the United States, there are several clinical trial
s currently going on that seek to verify whether nelfinavir is effective as a cancer therapeutic agent in humans. In some of these trials, nelfinavir is used alone in monotherapy fashion, whereas in others it is combined with other modes of cancer therapy, such as well-established chemotherapeutic agents or radiation therapy
.
Good phase I results were obtained for locally advanced pancreatic cancer
.
In the UK, a phase I trial (of nelfinavir with radiotherapy) on patients with inoperable cancer showed a doubling of survival times, and six patients had tumor regression to the extent that they became operable.
. Most interactions occur at the level of the Cytochrome P450
isozymes 3A4
and CYP2C19
, by which nelfinavir is metabolised.
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
used in the treatment of the human immunodeficiency virus (HIV). Nelfinavir belongs to the class of drugs known as protease inhibitors
Protease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
(PIs) and like other PIs is generally used in combination with other antiretroviral drugs.
Nelfinavir mesylate (Viracept, formally AG1343) is a potent and orally bioavailable human immunodeficiency virus HIV-1 protease
HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
inhibitor (Ki=2nM) and is being widely prescribed in combination with HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
reverse transcriptase inhibitors for the treatment of HIV infection.
History
Nelfinavir was developed by Agouron Pharmaceuticals as part of a joint venture with Japan Tobacco. Agouron Pharmaceuticals was acquired by Warner Lambert in 1999 and is now a subsidiary of Pfizer. It is marketed in Europe by Hoffman-La Roche and elsewhere by ViiV HealthcareViiV Healthcare
ViiV Healthcare is a pharmaceutical company specializing in the development of therapies for HIV that was created as a joint venture by Pfizer and GlaxoSmithKline in November 2009 with both companies transferring their HIV assets to the new company. 85% of the company is owned by GlaxoSmithKline...
.
The U.S. Food and Drug Administration (FDA) approved it for therapeutic use on March 14, 1997, making it the twelfth approved antiretroviral. The initial product launched proved to be the largest "biotech launch" in the history of the pharmaceutical industry achieving first full year sales exceeding $335M US. Agouron's patent
Patent
A patent is a form of intellectual property. It consists of a set of exclusive rights granted by a sovereign state to an inventor or their assignee for a limited period of time in exchange for the public disclosure of an invention....
on the drug will expire in 2014.
On the 6 June 2007, both the Medicines and Healthcare products Regulatory Agency
Medicines and Healthcare products Regulatory Agency
The Medicines and Healthcare products Regulatory Agency is the UK government agency which is responsible for ensuring that medicines and medical devices work and are acceptably safe....
and the European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
put out an alert requesting the recall of any of the drug in circulation because of fears that batches of the therapy may have been contaminated with potentially cancer-causing chemicals
Pharmacology
Nelfinavir should be taken with food. The bioavailability of Nelfinavir is increased 2.5 to 5 times when taken with food. Taking the drug with food also decreases the risk of diarrheaDiarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
as a side effect.
Mode of action
Nelfinavir is a protease inhibitorProtease inhibitor (pharmacology)
Protease inhibitors are a class of drugs used to treat or prevent infection by viruses, including HIV and Hepatitis C. PIs prevent viral replication by inhibiting the activity of proteases, e.g.HIV-1 protease, enzymes used by the viruses to cleave nascent proteins for final assembly of new...
: it inhibits HIV-1
HIV-1 protease
HIV-1 protease is a retroviral aspartyl protease that is essential for the life-cycle of HIV, the retrovirus that causes AIDS.HIV PR cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion...
and HIV-2 proteases. This protease is an enzyme which cleaves viral protein molecules into smaller fragments, and it is vital for both the replication of the virus within the cell and also the release of mature viral particles from an infected cell. Though this mode of action is common to all protease inhibitors, the precise mode of binding of nelfinavir to the enzyme may be sufficiently unique to reduce cross-resistance between it and other PIs. Also, not all PIs inhibit both HIV-1 and HIV-2 proteases.
Toxicity
Nelfinavir can produce a range of adverse effects. Common (experienced by more than one in one hundred patients; greater than 1%) are flatulence, diarrheaDiarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
or abdominal pain. Infrequent (experienced by one in one thousand to one in one hundred patients; 0.01 - 0.1%) adverse effects are fatigue, urination, rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...
, mouth ulcer
Mouth ulcer
A mouth or oral ulcer is an open sore in the mouth, or rarely a break in the mucous membrane or the epithelium on the lips or surrounding the mouth. The types of mouth ulcers are diverse, with a multitude of associated causes including: physical abrasion, acidic fruit, infection, other medical...
s or hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
. Rarely (less than one in one thousand patients; under 0.01%) nephrolithiasis, arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....
, Leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...
or allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
reactions may occur.
Potential anti-cancer activity
Nelfinavir is currently under investigation for potential use as an anti-cancer agent. When applied to cancer cells in culture (in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
), it is able to inhibit the growth of a variety of different cancer types and triggers cell death (apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
).
When Nelfinavir was given to laboratory mice with tumors of the prostate or of the brain, it could suppress tumor growth in these animals. In vitro tests showed it may work well with sorafenib
Sorafenib
Sorafenib , is a drug approved for the treatment of primary kidney cancer and advanced primary liver cancer ....
In the United States, there are several clinical trial
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s currently going on that seek to verify whether nelfinavir is effective as a cancer therapeutic agent in humans. In some of these trials, nelfinavir is used alone in monotherapy fashion, whereas in others it is combined with other modes of cancer therapy, such as well-established chemotherapeutic agents or radiation therapy
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
.
Good phase I results were obtained for locally advanced pancreatic cancer
Pancreatic cancer
Pancreatic cancer refers to a malignant neoplasm of the pancreas. The most common type of pancreatic cancer, accounting for 95% of these tumors is adenocarcinoma, which arises within the exocrine component of the pancreas. A minority arises from the islet cells and is classified as a...
.
In the UK, a phase I trial (of nelfinavir with radiotherapy) on patients with inoperable cancer showed a doubling of survival times, and six patients had tumor regression to the extent that they became operable.
Interactions
Nelfinavir's interaction profile is similar to that of other protease inhibitorsAntiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
. Most interactions occur at the level of the Cytochrome P450
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
isozymes 3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
and CYP2C19
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
, by which nelfinavir is metabolised.