Didanosine: Difference between revisions

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			{{Short description\|Chemical compound}}
	{{Drugbox
			{{Use dmy dates\|date=September 2024}}
	\| verifiedrevid = 443636866
			{{cs1 config \|name-list-style=vanc \|display-authors=6}}
	\| IUPAC_name = 9--6,9-dihydro-3''H''-purin-6-one
			{{Infobox drug
			\| Watchedfields = changed
			\| verifiedrevid = 458775891
	\| image = Didanosin.svg		\| image = Didanosin.svg
	\| width = ~~220~~		\| width = 200
			\| alt =
			\| image2 = Didanosine ball-and-stick model.png
			\| alt2 =

	<!--Clinical data-->		<!--Clinical data-->
	\| tradename =		\| tradename = Videx, Videx EC
	\| Drugs.com = {{drugs.com\|monograph\|didanosine}}		\| Drugs.com = {{drugs.com\|monograph\|didanosine}}
	\| MedlinePlus = a691006		\| MedlinePlus = a691006
	\| pregnancy_AU = B2		\| pregnancy_AU = B2
			\| routes_of_administration = ]
	\| pregnancy_US = B
			\| ATC_prefix = J05
			\| ATC_suffix = AF02
			\| ATC_supplemental =

	\| legal_UK = POM		\| legal_UK = POM
	\| legal_US = Rx-only		\| legal_US = Rx-only
	\| routes_of_administration = Oral

	<!--Pharmacokinetic data-->		<!--Pharmacokinetic data-->
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	\| protein_bound = Less than 5%		\| protein_bound = Less than 5%
	\| elimination_half-life = 1.5 hours		\| elimination_half-life = 1.5 hours
	\| excretion = ]		\| excretion = ]

	<!--Identifiers-->		<!--Identifiers-->
			\| IUPHAR_ligand = 4833
	\| CASNo_Ref = {{cascite\|correct\|CAS}}
	\| CAS_number_Ref = {{cascite\|correct\|??}}		\| CAS_number_Ref = {{cascite\|correct\|??}}
	\| CAS_number = 69655-05-6		\| CAS_number = 69655-05-6
	\| ~~ATC_prefix~~ = ~~J05~~		\| PubChem = 135398739
	\| ATC_suffix = AF02
	\| ATC_supplemental =
	\| PubChem = 50599
	\| DrugBank_Ref = {{drugbankcite\|correct\|drugbank}}		\| DrugBank_Ref = {{drugbankcite\|correct\|drugbank}}
	\| DrugBank = DB00900		\| DrugBank = DB00900
Line 41:		Line 47:
	\| ChEMBL_Ref = {{ebicite\|correct\|EBI}}		\| ChEMBL_Ref = {{ebicite\|correct\|EBI}}
	\| ChEMBL = 1460		\| ChEMBL = 1460
			\| NIAID_ChemDB = 000004
			\| synonyms = 2′,3′-dideoxyinosine, DDI

	<!--Chemical data-->		<!--Chemical data-->
			\| 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
			\| C=10 \| H=12 \| N=4 \| O=3
	\| molecular_weight = 236.227 g/mol
	\| smiles = O=C3/N=C\Nc1c3ncn12O(CC2)CO		\| smiles = O=C3/N=C\Nc1c3ncn12O(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_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		\| 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 59:
	\| StdInChIKey = BXZVVICBKDXVGW-NKWVEPMBSA-N		\| StdInChIKey = BXZVVICBKDXVGW-NKWVEPMBSA-N
	}}		}}
	'''Didanosine''' (2',3'-dideoxyinosine, '''ddI''', '''DDI''') is sold under the trade names '''Videx''' and '''Videx EC'''. It is a ], effective against ] and used in combination with other ] therapy as part of highly active antiretroviral therapy (HAART).

			'''Didanosine''', sold under the brand name '''Videx''' among others, is a ] used to treat ].<ref>{{Cite news\|url=https://www.medicinenet.com/didanosine/article.htm \|title=didanosine, Videx, Videx EC: Drug Facts, Side Effects and Dosing\|work=MedicineNet\|access-date=8 August 2018}}</ref> It is used in combination with other medications as part of ] (HAART). It is of the ] 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, ], ], and ] in the ] (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 ] (NIH) awarded a ten-year exclusive licensed to ] Co. (BMS) to market and sell ddI as Videx tablets.

			<!-- Society and culture -->
	Didanosine became the second drug approved for the treatment of HIV infection in many other countries, including in the United States by the ] (FDA) on October 9, 1991. Its FDA approval helped bring down the price of ] (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 ] 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 ], ], ], ], ], ], and ].<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=8 August 2018\|language=en-US}}</ref> Peripheral ] occurred in 21-26% of participants in key didanosine trials.<ref name="Videxpi" />

			] is rarely observed but has caused occasional fatalities, and has ] 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=8 August 2018}}</ref> Other reported serious adverse events are retinal changes, ] 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 ] issued a statement that patients using didanosine (Videx) are at risk for a rare but potentially fatal liver disorder, non-] 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 ], and administration of these drugs together should be avoided.<ref name="Videxpi" />
			*Reduction in ] and ] plasma levels have been shown to occur when administered simultaneously with didanosine; these drugs should be administered at different times.<ref name="Videxpi" />
			*], ], ] 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 ] and ], 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 = 4 May 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=6 May 2006 }}</ref>
			*] 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 ] (ZDV). The most common mutation observed ''in vivo'' is L74V in the viral ''pol'' gene, which confers cross-resistance to ]; 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==		==Mechanism of action==
	Didanosine (ddI) is a ] ] of ]. It differs from other nucleoside analogues, because it does not have any of the regular bases, instead it has ] 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 ] by competing with natural ].		Didanosine (ddI) is a ] ] of ].<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 ] 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 ] by competing with natural ].

	==Pharmacokinetics==		==Pharmacokinetics==
	Oral absorption of didanosine is fairly low (42%)<ref name="Videxpi"></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==
			{{refimprove section\|date=September 2024}}
	*A significant interaction has also been recorded with ], and administration of these drugs together should be avoided.<ref name="Videxpi" />
	*] and ] show reduced in plasma levels when administered simultaneously with didanosine; these drugs should be administered at different times.<ref name="Videxpi" />
	*], ], ] 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 ] and ], 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 )</ref>
	*] can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.<ref name="Videxpi" />

			The related ] 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, ], ], and ] in the ] (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 ] (NIH) awarded a ten-year exclusive license to ] Co. (BMS) to market and sell ddI as Videx tablets.
	==Adverse effects==
	The most common adverse events with didanosine are ], ], ], ], ], ] and ]. Peripheral ] occurred in 21-26% of participants in key didanosine trials.<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 ] (FDA) on 9 October 1991. Its FDA approval helped bring down the price of ] (ZDV), the initial anti-HIV drug.{{cn\|date=February 2024}}
	] is rarely observed but has caused occasional fatalities, and has ] status. Other reported serious adverse events are retinal changes, ] and alterations of liver functions. The risk of some of these serious adverse events is increased by drinking alcohol.

			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 ] 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.
	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>

			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.
	==Resistance==
	Drug resistance to didanosine does develop, though slower than to ] (AZT). The most common mutation observed ''in vivo'' is L74V in the viral ''pol'' gene, which confers cross-resistance to ]; 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>

			One of the patents for ddI expired in the United States on 29 August 2006, but other patents extend beyond that time.
	==Sources==
	<references />

	==~~Further~~ ~~reading~~==		== References ==
			{{Reflist}}
	* 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 4''<sup>th</sup> 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.
	*
	*
	*
	*

			== Further reading ==
	{{HIVpharm}}
			{{refbegin}}
			* {{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 }}
			* {{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 }}
			* {{cite book \| vauthors = Männistö PT, Tuominen RK \| title = Farmakologia ja Toksikologia \| edition = 5th \| veditors = Koulu M, Tuomisto J, Paasonen MK \| publisher = Medicina \| date = 1996 }}
			* {{cite book \| vauthors = Rang HP, Dale MM, Ritter JM \| title = Pharmacology \| edition = 3rd \| publisher = Pearson Professional Ltd \| date = 1995 }}
			* {{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}}
			* {{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 }}
			* {{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 }}
			* {{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 = 2 February 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 = 3 April 1998 \| work = Office of NIH History }}
			* {{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 = 30 September 2006 }}
			{{refend}}

			{{Antiretroviral drug}}
	''
			{{Portal bar \| Medicine \| Viruses }}
			{{Authority control}}

	]		]
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Latest revision as of 23:06, 21 September 2024

Chemical compound

Pharmaceutical compound

Didanosine
Clinical data


Trade names	Videx, Videx EC
Other names	2′,3′-dideoxyinosine, DDI
AHFS/Drugs.com	Monograph
MedlinePlus	a691006
Pregnancy category	AU: B2
Routes of administration	By mouth
ATC code	J05AF02 (WHO)
Legal status
Legal status	UK: POM (Prescription only) US: WARNINGRx-only
Pharmacokinetic data
Bioavailability	30 to 54%
Protein binding	Less than 5%
Elimination half-life	1.5 hours
Excretion	Kidney
Identifiers
IUPAC name 9-((2R,5S)-5-(hydroxymethyl)tetrahydrofuran-2-yl)-3H-purin-6(9H)-one
CAS Number	69655-05-6
PubChem CID	135398739
IUPHAR/BPS	4833
DrugBank	DB00900
ChemSpider	45864
UNII	K3GDH6OH08
KEGG	D00296
ChEBI	CHEBI:490877
ChEMBL	ChEMBL1460
NIAID ChemDB	000004
CompTox Dashboard (EPA)	DTXSID6022927
ECHA InfoCard	100.129.182
Chemical and physical data
Formula	C₁₀H₁₂N₄O₃
Molar mass	236.231 g·mol
3D model (JSmol)	Interactive image
SMILES O=C3/N=C\Nc1c3ncn12O(CC2)CO
InChI InChI=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 Key:BXZVVICBKDXVGW-NKWVEPMBSA-N
(verify)

Didanosine, sold under the brand name Videx among others, is a medication used to treat HIV/AIDS. It is used in combination with other medications as part of highly active antiretroviral therapy (HAART). It is of the reverse-transcriptase inhibitor class.

Didanosine was first described in 1975 and approved for use in the United States in 1991.

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.

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 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.

Drug interactions

A significant interaction has also been recorded with allopurinol, and administration of these drugs together should be avoided.
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.
Ketoconazole, itraconazole, ciprofloxacin 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 stavudine, is not recommended.
Alcohol can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.

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 .

Mechanism of action

Didanosine (ddI) is a nucleoside analogue of adenosine. 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.

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.

History

This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources in this section. Unsourced material may be challenged and removed. (September 2024) (Learn how and when to remove this message)

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 license 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 9 October 1991. Its FDA approval helped bring down the price of zidovudine (ZDV), 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 29 August 2006, but other patents extend beyond that time.

References

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"Didanosine Videx - Treatment - National HIV Curriculum". www.hiv.uw.edu. Retrieved 8 August 2018.
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DHHS Panel (4 May 2006). "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents". AIDSInfo. U.S. Department of Health and Human Services. Archived from the original on 6 May 2006.
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Pruvost A, Negredo E, Benech H, Theodoro F, Puig J, Grau E, et al. (May 2005). "Measurement of intracellular didanosine and tenofovir phosphorylated metabolites and possible interaction of the two drugs in human immunodeficiency virus-infected patients". Antimicrobial Agents and Chemotherapy. 49 (5): 1907–14. doi:10.1128/AAC.49.5.1907-1914.2005. PMC 1087635. PMID 15855513.{{cite journal}}: CS1 maint: overridden setting (link)