Didanosine
Encyclopedia
Didanosine is sold under the trade names Videx and Videx EC. It is a reverse transcriptase inhibitor
, effective against HIV
and used in combination with other antiretroviral drug
therapy as part of highly active antiretroviral therapy (HAART).
, Hiroaki Mitsuya
, and Robert Yarchoan
in the National Cancer Institute
(NCI) found that ddA and ddI could inhibit HIV replication in the test tube and conducted initial clinical trials showing that didanosine had activity in patients infected with HIV. On behalf of the NCI, they were awarded patents on these activities. Since the NCI does not market products directly, the National Institutes of Health
(NIH) awarded a ten-year exclusive licensed to Bristol-Myers Squibb
Co. (BMS) to market and sell ddI as Videx tablets.
Didanosine became the second drug approved for the treatment of HIV infection in many other countries, including in the United States by the Food and Drug Administration
(FDA) on October 9, 1991. Its FDA approval helped bring down the price of zidovudine
(AZT), the initial anti-HIV drug.
Didanosine has weak acid stability and is easily damaged by stomach acid. Therefore, the original formula approved by the FDA used chewable tablets that included an antacid
buffering compound to neutralize stomach acid. The chewable tablets were not only large and fragile, they also were foul-tasting and the buffering compound would cause diarrhea. Although the FDA had not approved the original formulation for once-a-day dosing it was possible for some people to take it that way.
At the end of its ten-year license, BMS re-formulated Videx as Videx EC and patented that, which reformulation the FDA approved in 2000. The new formulation is a smaller capsule containing coated microspheres instead of using a buffering compound. It is approved by the FDA for once-a-day dosing. Also at the end of that ten-year period, the NIH licensed didanosine to Barr Laboratories under a non-exclusive license, and didanosine became the first generic anti-HIV drug marketed in the United States.
One of the patents for ddI expired in the United States on 2006-08-29, but other patents extend beyond that time.
analogue
of guanosine
. It differs from other nucleoside analogues, because it does not have any of the regular bases, instead it has hypoxanthine
attached to the sugar ring. Within the cell, ddI is phosphorylated to the active metabolite of dideoxyadenosine triphosphate, ddATP, by cellular enzymes. Like other anti-HIV nucleoside analogs, it acts as a chain terminator by incorporation and inhibits viral reverse transcriptase
by competing with natural dATP
.
, nausea
, vomiting
, abdominal pain
, fever
, headache
and rash
. Peripheral neuropathy occurred in 21-26% of participants in key didanosine trials.
Pancreatitis
is rarely observed but has caused occasional fatalities, and has black box warning
status. Other reported serious adverse events are retinal changes, optic neuritis
and alterations of liver functions. The risk of some of these serious adverse events is increased by drinking alcohol.
In February of 2010, the United States Food and Drug Administration issued a statement that patients using Didanosine (Videx) are at risk for a rare
but potentially fatal liver disorder, non-cirrhotic portal hypertension.
(AZT). The most common mutation observed in vivo is L74V in the viral pol gene, which confers cross-resistance to zalcitabine; other mutations observed include K65R and M184V .
Reverse transcriptase inhibitor
Reverse-transcriptase inhibitors are a class of antiretroviral drug used to treat HIV infection, tumors, and cancer. RTIs inhibit activity of reverse transcriptase, a viral DNA polymerase enzyme that retroviruses need to reproduce.-Mechanism:...
, effective against 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...
and used in combination with other antiretroviral drug
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...
therapy as part of highly active antiretroviral therapy (HAART).
History
The related pro-drug of didanosine, 2'3'-dideoxyadenosine (ddA), was initially synthesized by Morris J. Robins (professor of Organic Chemistry at Brigham Young University) and R.K. Robins in 1964. Subsequently, Samuel BroderSamuel Broder
Samuel Broder is an American oncologist and medical researcher. He was a co-developer of some of the first effective drugs for the treatment of AIDS and was Director of the National Cancer Institute from 1989 to 1995....
, Hiroaki Mitsuya
Hiroaki Mitsuya
is a Japanese virologist famous for his role in discovery of the anti-HIV drug zidovudine as well as other anti-AIDS drugs including didanosine and zalcitabine . Mitsuya obtained his M.D. and Ph.D. at Kumamoto University in Japan...
, and Robert Yarchoan
Robert Yarchoan
Robert Yarchoan is a medical researcher who played an important role in the development of the first effective drugs for AIDS. He is the Chief of the HIV and AIDS Malignancy Branch in the NCI and also coordinates AIDS and AIDS malignancy research throughout the NCI as Director of the Office of HIV...
in the National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
(NCI) found that ddA and ddI could inhibit HIV replication in the test tube and conducted initial clinical trials showing that didanosine had activity in patients infected with HIV. On behalf of the NCI, they were awarded patents on these activities. Since the NCI does not market products directly, the National Institutes of Health
National Institutes of Health
The National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
(NIH) awarded a ten-year exclusive licensed to Bristol-Myers Squibb
Bristol-Myers Squibb
Bristol-Myers Squibb , often referred to as BMS, is a pharmaceutical company, headquartered in New York City. The company was formed in 1989, following the merger of its predecessors Bristol-Myers and the Squibb Corporation...
Co. (BMS) to market and sell ddI as Videx tablets.
Didanosine became the second drug approved for the treatment of HIV infection in many other countries, including in the United States by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) on October 9, 1991. Its FDA approval helped bring down the price of zidovudine
Zidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(AZT), the initial anti-HIV drug.
Didanosine has weak acid stability and is easily damaged by stomach acid. Therefore, the original formula approved by the FDA used chewable tablets that included an antacid
Antacid
An antacid is a substance which neutralizes stomach acidity.-Mechanism of action:Antacids perform a neutralization reaction, increasing the pH to reduce acidity in the stomach. When gastric hydrochloric acid reaches the nerves in the gastrointestinal mucosa, they signal pain to the central nervous...
buffering compound to neutralize stomach acid. The chewable tablets were not only large and fragile, they also were foul-tasting and the buffering compound would cause diarrhea. Although the FDA had not approved the original formulation for once-a-day dosing it was possible for some people to take it that way.
At the end of its ten-year license, BMS re-formulated Videx as Videx EC and patented that, which reformulation the FDA approved in 2000. The new formulation is a smaller capsule containing coated microspheres instead of using a buffering compound. It is approved by the FDA for once-a-day dosing. Also at the end of that ten-year period, the NIH licensed didanosine to Barr Laboratories under a non-exclusive license, and didanosine became the first generic anti-HIV drug marketed in the United States.
One of the patents for ddI expired in the United States on 2006-08-29, but other patents extend beyond that time.
Mechanism of action
Didanosine (ddI) is a nucleosideNucleoside
Nucleosides are glycosylamines consisting of a nucleobase bound to a ribose or deoxyribose sugar via a beta-glycosidic linkage...
analogue
Analog (chemistry)
In chemistry, a structural analog , also known as chemical analog or simply analog, is a compound having a structure similar to that of another one, but differing from it in respect of a certain component. It can differ in one or more atoms, functional groups, or substructures, which are replaced...
of guanosine
Guanosine
Guanosine is a purine nucleoside comprising guanine attached to a ribose ring via a β-N9-glycosidic bond. Guanosine can be phosphorylated to become guanosine monophosphate , cyclic guanosine monophosphate , guanosine diphosphate , and guanosine triphosphate...
. It differs from other nucleoside analogues, because it does not have any of the regular bases, instead it has hypoxanthine
Hypoxanthine
Hypoxanthine is a naturally occurring purine derivative. It is occasionally found as a constituent of nucleic acids where it is present in the anticodon of tRNA in the form of its nucleoside inosine. It has a tautomer known as 6-Hydroxypurine. Hypoxanthine is a necessary additive in certain cell,...
attached to the sugar ring. Within the cell, ddI is phosphorylated to the active metabolite of dideoxyadenosine triphosphate, ddATP, by cellular enzymes. Like other anti-HIV nucleoside analogs, it acts as a chain terminator by incorporation and inhibits viral reverse transcriptase
Reverse transcriptase
In the fields of molecular biology and biochemistry, a reverse transcriptase, also known as RNA-dependent DNA polymerase, is a DNA polymerase enzyme that transcribes single-stranded RNA into single-stranded DNA. It also helps in the formation of a double helix DNA once the RNA has been reverse...
by competing with natural dATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
.
Pharmacokinetics
Oral absorption of didanosine is fairly low (42%) but rapid. Food substantially reduces didanosine bioavailability, and the drug should be administered on an empty stomach. The half-life in plasma is only 1.5 hours, but in the intracellular environment more than 12 hours. An enteric-coated formulation is now marketed as well. Elimination is predominantly renal; the kidneys actively secrete didanosine, the amount being 20% of the oral dose.Drug interactions
- A significant interaction has also been recorded with allopurinolAllopurinolAllopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
, and administration of these drugs together should be avoided. - IndinavirIndinavirIndinavir is a protease inhibitor used as a component of highly active antiretroviral therapy to treat HIV infection and AIDS.-History:...
and delavirdineDelavirdineDelavirdine is a non-nucleoside reverse transcriptase inhibitor marketed by ViiV Healthcare. It is used as part of highly active antiretroviral therapy for the treatment of human immunodeficiency virus type 1. It is presented as the mesylate...
show reduced in plasma levels when administered simultaneously with didanosine; these drugs should be administered at different times. - KetoconazoleKetoconazoleKetoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, itraconazoleItraconazoleItraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, ciprofloxacinCiprofloxacinCiprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
should be administered at a different time from didanosine due to interactions with the buffering agent. - Administration with drugs with overlapping toxicity, such as zalcitabine and stavudineStavudineStavudine is a nucleoside analog reverse transcriptase inhibitor active against HIV.-History:...
, is not recommended. - AlcoholAlcoholIn chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.
Adverse effects
The most common adverse events with didanosine are 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...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, abdominal pain
Abdominal pain
Abdominal pain can be one of the symptoms associated with transient disorders or serious disease. Making a definitive diagnosis of the cause of abdominal pain can be difficult, because many diseases can result in this symptom. Abdominal pain is a common problem...
, fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
and 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...
. Peripheral neuropathy occurred in 21-26% of participants in key didanosine trials.
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...
is rarely observed but has caused occasional fatalities, and has black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
status. Other reported serious adverse events are retinal changes, optic neuritis
Optic neuritis
Optic neuritis is the inflammation of the optic nerve that may cause a complete or partial loss of vision.-Causes:The optic nerve comprises axons that emerge from the retina of the eye and carry visual information to the primary visual nuclei, most of which is relayed to the occipital cortex of the...
and alterations of liver functions. The risk of some of these serious adverse events is increased by drinking alcohol.
In February of 2010, the United States Food and Drug Administration issued a statement that patients using Didanosine (Videx) are at risk for a rare
but potentially fatal liver disorder, non-cirrhotic portal hypertension.
Resistance
Drug resistance to didanosine does develop, though slower than to zidovudineZidovudine
Zidovudine or azidothymidine is a nucleoside analog reverse-transcriptase inhibitor , a type of antiretroviral drug used for the treatment of HIV/AIDS. It is an analog of thymidine....
(AZT). The most common mutation observed in vivo is L74V in the viral pol gene, which confers cross-resistance to zalcitabine; other mutations observed include K65R and M184V .
Further reading
- Robins MJ, McCarthy JR Jr., Robins RJ. Biochemistry 1966; 5(1):224-31.
- Yarchoan R, Mitsuya H, Broder S. AIDS therapies. Sci Am 1988;259(4):110-9.
- Männistö P.T., Tuominen R.K. in Farmakologia ja Toksikologia, 5th edition: (ed. Koulu, Tuomisto, Paasonen) Medicina, 1996.
- Rang H.P., Dale M.M., Ritter J.M.: Pharmacology, 3rd edition. Pearson Professional Ltd, 1995.
- Watson et al.: Molecular Biology of the Gene 4th edition. The Benjamin/Cummings Publishing Company, 1987.
- Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. Science 1990;249(4976):1533-44.
- Yarchoan R, Mitsuya H, Thomas RV, et al. In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine. Science 1989;245(4916):412-5.
- NIH Oral History of Samuel Broder describing development of AIDS drugs
- NIH Oral History of Robert Yarchoan describing development of AIDS drugs
- NIH Office of Technology Transfer Report on Development and Licensing of ddI
- FDA reviews safety of two HIV drugs