Didanosine: Difference between revisions

(92 intermediate revisions by 59 users not shown)

Line 1:

{{Drugbox

{{Infobox drug

| verifiedrevid = 443636866

| Watchedfields = changed

| IUPAC_name = 9-[(2''R'',5''S'')-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-3''H''-purin-6-one

| verifiedrevid = 458775891

| image = Didanosin.svg

| width = ~~220~~

| width = 200

| alt =

| image2 = Didanosine ball-and-stick model.png

| alt2 =

| tradename =

| tradename = Videx

| Drugs.com = {{drugs.com|monograph|didanosine}}

| MedlinePlus = a691006

| pregnancy_AU = B2

| pregnancy_US = B

| legal_UK = POM

| legal_US = Rx-only

| routes_of_administration = Oral

| routes_of_administration = [[Oral administration|By mouth]]

| ATC_prefix = J05

| ATC_suffix = AF02

| ATC_supplemental =

Line 19:

Line 25:

| protein_bound = Less than 5%

| elimination_half-life = 1.5 hours

| excretion = [[Kidney~~|Renal~~]]

| excretion = [[Kidney]]

| IUPHAR_ligand = 4833

| CASNo_Ref = {{cascite|correct|CAS}}

| CAS_number_Ref = {{cascite|correct|??}}

| CAS_number = 69655-05-6

| ~~ATC_prefix~~ = ~~J05~~

| PubChem = 135398739

| ATC_suffix = AF02

| ATC_supplemental =

| PubChem = 50599

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| DrugBank = DB00900

Line 41:

Line 44:

| ChEMBL_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1460

| NIAID_ChemDB = 000004

| synonyms = 2′,3′-dideoxyinosine

| IUPAC_name = 9-((2''R'',5''S'')-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3''H''-purin-6(9''H'')-one

| C=10 | H=12 | N=4 | O=3

| molecular_weight = 236.227 g/mol

| smiles = O=C3/N=C\Nc1c3ncn1[C@@H]2O[C@@H](CC2)CO

| InChI = 1/C10H12N4O3/c15-3-6-1-2-7(17-6)14-5-13-8-9(14)11-4-12-10(8)16/h4-7,15H,1-3H2,(H,11,12,16)/t6-,7+/m0/s1

| InChIKey = BXZVVICBKDXVGW-NKWVEPMBBL

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| StdInChI = 1S/C10H12N4O3/c15-3-6-1-2-7(17-6)14-5-13-8-9(14)11-4-12-10(8)16/h4-7,15H,1-3H2,(H,11,12,16)/t6-,7+/m0/s1

Line 53:

Line 56:

| StdInChIKey = BXZVVICBKDXVGW-NKWVEPMBSA-N

}}

'''Didanosine''' (2',3'-dideoxyinosine, '''ddI''', '''DDI''') 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).

'''Didanosine''' ('''ddI''', '''DDI'''), sold under the brand name '''Videx''', is a [[medication]] used to treat [[HIV/AIDS]].<ref>{{Cite news|url=https://www.medicinenet.com/didanosine/article.htm#is_didanosine_available_as_a_generic_drug?|title=didanosine, Videx, Videx EC: Drug Facts, Side Effects and Dosing|work=MedicineNet|access-date=2018-08-08|language=en}}</ref> It is used in combination with other medications as part of [[highly active antiretroviral therapy]] (HAART). It is of the [[reverse-transcriptase inhibitor]] class.

==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 Broder]], [[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 was first described in 1975 and approved for use in the United States in 1991.<ref>{{cite book| vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery|date=2006|publisher=John Wiley & Sons|isbn=9783527607495|page=505|url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA505|language=en}}</ref>

==Adverse effects==

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.

The most common adverse events with didanosine are [[diarrhea]], [[nausea]], [[vomiting]], [[abdominal pain]], [[fever]], [[headache]], and [[rash]].<ref>{{Cite news|url=https://www.drugs.com/sfx/didanosine-side-effects.html|title=Didanosine Side Effects in Detail - Drugs.com|work=Drugs.com|access-date=2018-08-08|language=en-US}}</ref> Peripheral [[neuropathy]] occurred in 21-26% of participants in key didanosine trials.<ref name="Videxpi" />

[[Pancreatitis]] is rarely observed but has caused occasional fatalities, and has [[black box warning]] status.<ref>{{Cite web|url=https://www.hiv.uw.edu/page/treatment/drugs/didanosine|title=Didanosine Videx - Treatment - National HIV Curriculum|website=www.hiv.uw.edu|language=en|access-date=2018-08-08}}</ref> 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.

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.

In February 2010, the [[Food and Drug Administration|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-[[Cirrhosis|cirrhotic]] portal hypertension.<ref>{{cite web | title = Serious liver disorder associated with the use of Videx/Videx EC (didanosine)| url = https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/fda-drug-safety-communication-serious-liver-disorder-associated-use-videxvidex-ec-didanosine | work = FDA Drug Safety Communication | publisher = U.S. Food and Drug Administration | date = 19 January 2010 }}</ref>

One of the patents for ddI expired in the United States on 2006-08-29, but other patents extend beyond that time.

==Drug interactions==

*A significant interaction has also been recorded with [[allopurinol]], and administration of these drugs together should be avoided.<ref name="Videxpi" />

*Reduction in [[indinavir]] and [[delavirdine]] plasma levels have been shown to occur when administered simultaneously with didanosine; these drugs should be administered at different times.<ref name="Videxpi" />

*[[Ketoconazole]], [[itraconazole]], [[ciprofloxacin]] should be administered at a different time from didanosine due to interactions with the buffering agent.<ref name="Videxpi" />

*Administration with drugs with overlapping toxicity, such as [[zalcitabine]] and [[stavudine]], is not recommended.<ref name="dhhs">{{cite web | author = DHHS Panel | title = Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents | date = May 4, 2006 | url = http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 | work = AIDSInfo | publisher = U.S. Department of Health and Human Services | archive-url = https://web.archive.org/web/20060506193229/http://aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 | archive-date=2006-05-06 }}</ref>

*[[ethanol|Alcohol]] can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.<ref name="Videxpi" />

==Resistance==

Drug resistance to didanosine does develop, though slower than to [[zidovudine]] (ZDV). 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 .<ref name="Videxpi" /><ref name="Moyle">{{cite journal | vauthors = Moyle GJ | title = Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences | journal = Drugs | volume = 52 | issue = 2 | pages = 168–85 | date = August 1996 | pmid = 8841736 | doi = 10.2165/00003495-199652020-00002 | s2cid = 27709969 }}</ref>

==Mechanism of action==

Didanosine (ddI) is a [[nucleoside]] [[~~analog~~ ~~(chemistry)~~|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 [[Adenosine triphosphate|dATP]].

Didanosine (ddI) is a [[nucleoside]] [[structural analog|analogue]] of [[adenosine]].<ref>{{cite journal | vauthors = Pruvost A, Negredo E, Benech H, Theodoro F, Puig J, Grau E, García E, Moltó J, Grassi J, Clotet B | display-authors = 6 | title = Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients | journal = Antimicrobial Agents and Chemotherapy | volume = 49 | issue = 5 | pages = 1907–14 | date = May 2005 | pmid = 15855513 | pmc = 1087635 | doi = 10.1128/AAC.49.5.1907-1914.2005 }}</ref> 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 [[Adenosine triphosphate|dATP]].

==Pharmacokinetics==

Oral absorption of didanosine is fairly low (42%)<ref name="Videxpi">[http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=VIDEX VIDEX (didanosine): chewable/dispersible buffered tablets; buffered powder for oral solution; pediatric powder for oral solution. ~~Product~~ ~~information~~ (July 2000)]</ref> but rapid. Food substantially reduces didanosine bioavailability, and the drug should be administered on an empty stomach.<ref name="Videxpi" /> The half-life in plasma is only 1.5 hours,<ref name="Videxpi" /> 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.

Oral absorption of didanosine is fairly low (42%)<ref name="Videxpi">{{cite web | url = http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=VIDEX | title = VIDEX (didanosine): chewable/dispersible buffered tablets; buffered powder for oral solution; pediatric powder for oral solution. | date = July 2000 | publisher = U.S. Food and Drug Administration }}</ref> but rapid. Food substantially reduces didanosine bioavailability, and the drug should be administered on an empty stomach.<ref name="Videxpi" /> The half-life in plasma is only 1.5 hours,<ref name="Videxpi" /> 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.

==History==

==Drug interactions==

The related [[Prodrug|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 Broder]], [[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 license to [[Bristol-Myers Squibb]] Co. (BMS) to market and sell ddI as Videx tablets.

*A significant interaction has also been recorded with [[allopurinol]], and administration of these drugs together should be avoided.<ref name="Videxpi" />

*[[Indinavir]] and [[delavirdine]] show reduced in plasma levels when administered simultaneously with didanosine; these drugs should be administered at different times.<ref name="Videxpi" />

*[[Ketoconazole]], [[itraconazole]], [[ciprofloxacin]] should be administered at a different time from didanosine due to interactions with the buffering agent.<ref name="Videxpi" />

*Administration with drugs with overlapping toxicity, such as [[zalcitabine]] and [[stavudine]], is not recommended.<ref name="dhhs"> DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from [http://www.aidsinfo.nih.gov/Guidelines/GuidelineDetail.aspx?MenuItem=Guidelines&Search=Off&GuidelineID=7&ClassID=1 AIDSInfo])</ref>

*[[Alcohol]] can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.<ref name="Videxpi" />

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]] (ZDV), the initial anti-HIV drug.{{cn|date=February 2024}}

==Adverse effects==

The most common adverse events with didanosine are [[diarrhea]], [[nausea]], [[vomiting]], [[abdominal pain]], [[fever]], [[headache]] and [[rash]]. Peripheral [[neuropathy]] occurred in 21-26% of participants in key didanosine trials.<ref name="Videxpi" />

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.

[[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.

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.

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.<ref>http://hosted.ap.org/dynamic/stories/U/US_HIV_DRUG_LIVER_RISKS?SITE=KYB66&SECTION=HOME&TEMPLATE=DEFAULT</ref>

One of the patents for ddI expired in the United States on August 29, 2006, but other patents extend beyond that time.

==Resistance==

Drug resistance to didanosine does develop, though slower than to [[zidovudine]] (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 .<ref name="Videxpi" /><ref name="Moyle">Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. ''Drugs'' 1996;52:168-185</ref>

==Sources==

==Further reading==

== Further reading ==

* Robins MJ, McCarthy JR Jr., Robins RJ. ''Biochemistry'' 1966; 5(1):224-31.

* {{cite journal | vauthors = Robins MJ, McCarthy JR, Robins RK | title = Purine nucleosides. XII. The preparation of 2',3'-dideoxyadenosine, 2',5'-dideoxyadenosine, and 2',3',5'-trideoxyadenosine from 2'-deoxyadenosine | journal = Biochemistry | volume = 5 | issue = 1 | pages = 224–31 | date = January 1966 | pmid = 5938940 | doi = 10.1021/bi00865a029 }}

* Yarchoan R, Mitsuya H, Broder S. AIDS therapies. ''Sci Am'' 1988;259(4):110-9.

* {{cite journal | vauthors = Yarchoan R, Mitsuya H, Broder S | title = AIDS therapies | journal = Scientific American | volume = 259 | issue = 4 | pages = 110–9 | date = October 1988 | pmid = 3072667 | doi = 10.1038/scientificamerican1088-110 | bibcode = 1988SciAm.259d.110Y }}

* Männistö P.T., Tuominen R.K. in ''Farmakologia ja Toksikologia'', 5th edition: (ed. Koulu, Tuomisto, Paasonen) Medicina, 1996.

* {{cite book | vauthors = Männistö PT, Tuominen RK | title = Farmakologia ja Toksikologia | edition = 5th | veditors = Koulu M, Tuomisto J, Paasonen MK | publisher = Medicina | date = 1996 }}

* Rang H.P., Dale M.M., Ritter J.M.: ''Pharmacology'', 3rd edition. Pearson Professional Ltd, 1995.

* {{cite book | vauthors = Rang HP, Dale MM, Ritter JM | title = Pharmacology | edition = 3rd | publisher = Pearson Professional Ltd | date = 1995 }}

* Watson ''et al.'': ''Molecular Biology of the Gene 4''<sup>th</sup> edition. The Benjamin/Cummings Publishing Company, 1987.

* {{cite book | vauthors = Watson JD, Hopkins NH, Roberts JW, Steitz JA, Weiner AM |title=Molecular Biology of the Gene |publisher=Benjamin/Cummings |isbn=978-0-8053-9612-6 |edition=4th | date = 1987}}

* Mitsuya H, Yarchoan R, Broder S. Molecular targets for AIDS therapy. ''Science'' 1990;249(4976):1533-44.

* {{cite journal | vauthors = Mitsuya H, Yarchoan R, Broder S | title = Molecular targets for AIDS therapy | journal = Science | volume = 249 | issue = 4976 | pages = 1533–44 | date = September 1990 | pmid = 1699273 | doi = 10.1126/science.1699273 | bibcode = 1990Sci...249.1533M | url = https://zenodo.org/record/1230944 }}

* 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.

* {{cite journal | vauthors = Yarchoan R, Mitsuya H, Thomas RV, Pluda JM, Hartman NR, Perno CF, Marczyk KS, Allain JP, Johns DG, Broder S | display-authors = 6 | title = In vivo activity against HIV and favorable toxicity profile of 2',3'-dideoxyinosine | journal = Science | volume = 245 | issue = 4916 | pages = 412–5 | date = July 1989 | pmid = 2502840 | doi = 10.1126/science.2502840 | bibcode = 1989Sci...245..412Y | url = https://zenodo.org/record/1231000 }}

* [http://history.nih.gov/NIHInOwnWords/docs/page_09.html NIH Oral History of Samuel Broder describing development of AIDS drugs]

* [http://history.nih.gov/NIHInOwnWords/docs/~~page_25~~.html NIH Oral History of ~~Robert~~ ~~Yarchoan~~ describing development of AIDS drugs]

* {{cite web | url = http://history.nih.gov/NIHInOwnWords/docs/page_09.html | title = NIH Oral History of Samuel Broder describing development of AIDS drugs | date = February 2, 1997 | work = Office of NIH History }}

* {{cite web | url = http://history.nih.gov/NIHInOwnWords/docs/page_25.html | title = NIH Oral History of Robert Yarchoan describing development of AIDS drugs | date = April 3, 1998 | work = Office of NIH History }}

* [http://ott.od.nih.gov/pdfs/VidexCS.pdf NIH Office of Technology Transfer Report on Development and Licensing of ddI]

* {{cite web | url = http://ott.od.nih.gov/pdfs/VidexCS.pdf | title = Report on Development and Licensing of ddI | date = September 2003 | work = National Institutes of Health Office of Technology Transfer | archive-url = https://web.archive.org/web/20060930022145/http://ott.od.nih.gov/pdfs/VidexCS.pdf | archive-date = 2006-09-30 }}

*[http://money.cnn.com/news/newsfeeds/articles/newstex/AFX-0013-24075973.htm FDA reviews safety of two HIV drugs]

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/didanosine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Didanosine }}

''

[[Category:Nucleoside analog reverse transcriptase inhibitors]]

[[Category:Purines]]

[[Category:~~Bristol-Myers Squibb~~]]

[[Category:Hepatotoxins]]

[[Category:~~World~~ ~~Health~~ ~~Organization~~ ~~essential~~ ~~medicines~~]]

[[Category:Drugs developed by Bristol Myers Squibb]]

[[Category:Hydroxymethyl compounds]]

[[de:Didanosin]]

[[es:Didanosina]]

[[fr:Didanosine]]

[[pt:Didanosina]]

[[sl:Didanozin]]

[[th:ไดดาโนซีน]]