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an antiviral drug used to combat HIV infection (同)ddI, DDI, didanosine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/02/20 11:41:38」(JST)

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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).

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 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.

Mechanism of action

Didanosine (ddI) is a nucleoside 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.

Pharmacokinetics

Oral absorption of didanosine is fairly low (42%)^[1] but rapid. Food substantially reduces didanosine bioavailability, and the drug should be administered on an empty stomach.^[1] The half-life in plasma is only 1.5 hours,^[1] 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 allopurinol, and administration of these drugs together should be avoided.^[1]
Indinavir and delavirdine show reduced in plasma levels when administered simultaneously with didanosine; these drugs should be administered at different times.^[1]
Ketoconazole, itraconazole, ciprofloxacin should be administered at a different time from didanosine due to interactions with the buffering agent.^[1]
Administration with drugs with overlapping toxicity, such as zalcitabine and stavudine, is not recommended.^[2]
Alcohol can exacerbate didanosine's toxicity, and avoiding drinking alcohol while taking didanosine is recommended.^[1]

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.^[1]

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.^[3]

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 .^[1]^[4]

Sources

^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ VIDEX (didanosine): chewable/dispersible buffered tablets; buffered powder for oral solution; pediatric powder for oral solution. Product information (July 2000)
^ DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo)
^ http://hosted.ap.org/dynamic/stories/U/US_HIV_DRUG_LIVER_RISKS?SITE=KYB66&SECTION=HOME&TEMPLATE=DEFAULT
^ Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. Drugs 1996;52:168-185

UpToDate Contents

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1. ヌクレオシド系逆転写酵素阻害剤の薬理学 pharmacology of nucleoside reverse transcriptase inhibitors
2. 抗レトロウイルス剤投与患者における悪性腫瘍に対する全身療法 systemic therapy for malignancy in patients on anti retroviral medications
3. HIV抗レトロウイルス療法に関する臨床試験：ヌクレオシド系逆転写酵素阻害剤を使用
した3剤療法 clinical trials of hiv antiretroviral therapy triple regimens using nucleoside reverse transcriptase inhibitors
4. 抗レトロウイルス療法の潜在的副作用に関するHIV感染患者を対象とした
カウンセリング counseling hiv infected patients regarding potential side effects of antiretroviral therapy
5. 未治療HIV感染患者のための選択的抗レトロウイルス療法 selecting antiretroviral regimens for the treatment naive hiv infected patient

English Journal

Abacavir induces loading of novel self-peptides into HLA-B*57: 01: an autoimmune model for HLA-associated drug hypersensitivity.

Norcross MA, Luo S, Lu L, Boyne MT, Gomarteli M, Rennels AD, Woodcock J, Margulies DH, McMurtrey C, Vernon S, Hildebrand WH, Buchli R.SourceaLaboratory of Immunology, Division of Therapeutic Proteins, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda bDivision of Pharmaceutical Analysis, Office of Testing and Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland cPure Protein, LLC, Oklahoma City, Oklahoma dOffice of the Center Director, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring eMolecular Biology Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland fDepartment of Microbiology and Immunology, School of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
AIDS (London, England).AIDS.2012 Jul 17;26(11):F21-F29.
BACKGROUND: Abacavir drug hypersensitivity in HIV-treated patients is associated with HLA-B57:01 expression. To understand the immunochemistry of abacavir drug reactions, we investigated the effects of abacavir on HLA-B57:01 epitope-binding in vitro and the quality and quantity of self-peptides pres
PMID 22617051

Improved Neuropsychological and Neurological Functioning Across Three Antiretroviral Regimens in Diverse Resource-Limited Settings: AIDS Clinical Trials Group Study A5199, the International Neurological Study.

Robertson K, Jiang H, Kumwenda J, Supparatpinyo K, Evans S, Campbell TB, Price R, Tripathy S, Kumarasamy N, La Rosa A, Santos B; the 5199 study team, Silva MT, Montano S, Kanyama C, Faesen S, Murphy R, Hall C, Marra CM, Marcus C, Berzins B, Allen R, Housseinipour M, Amod F, Sanne I, Hakim J, Walawander A, Nair A; and the AIDS Clinical Trials Group.SourceUniversity of North Carolina, Chapel Hill.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.Clin Infect Dis.2012 Jun 22. [Epub ahead of print]
Background. AIDS Clinical Trials Group (ACTG) A5199 compared the neurological and neuropsychological (NP) effects of 3 antiretroviral regimens in participants infected with human immunodeficiency virus type 1 (HIV-1) in resource-limited settings.Methods. Participants from Brazil, India, Malawi,
PMID 22661489

Japanese Journal

Influx mechanism of 2', 3'-dideoxyinosine (ddI) and uridine at the blood-placenta barrier

Sato K.,Sai Yoshimichi,Nishimura T.,Chishu T.,Kose N.,Nakashima E.
Placenta 30(3), 263-269, 2009-03-00
… 2′,3′-Dideoxyinosine (ddI) has a nucleoside structure, and crosses the BPB. …
NAID 120001893494

ヒト免疫不全ウイルス1型 (HIV-1) 感染者におけるHIV-1の逆転写酵素阻害剤に対する耐性変異

杉田哲佳
慶應醫學 74(1), 47-58, 1997-01-25
NAID 10011381701

Intestinal Absorption and First-Pass Elimination of 2', 3'-Dideoxynucleosides Following Oral Administration in Rats

HASEGAWA Tetsuya,JUNI Kazuhiko,SANEYOSHI Mineo,KAWAGUCHI Takeo
Biological & pharmaceutical bulletin 19(4), 599-603, 1996-04-15
… Intestinal absorption and first-pass elimination of 2', 3'-dideoxynucleosides (ddNs), including 3'-azido-3'-deoxythymidine (AZT), 2', 3'-dideoxyinosine (DDI) and 2', 3'-didehydro-3'-deoxythymidine (D4T), following oral administration was investigated in rats. …
NAID 110003641221

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★リンクテーブル★

リンク元	「ジダノシン」「ジデオキシイノシン」

「ジダノシン」

Didanosine
Systematic (IUPAC) name
	9-[(2R,5S)-5-(hydroxymethyl)oxolan-2-yl]-6,9-dihydro-3H-purin-6-one
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a691006
Pregnancy cat.	B2(AU) B(US)
Legal status	POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	30 to 54%
Protein binding	Less than 5%
Half-life	1.5 hours
Excretion	Renal
Identifiers
CAS number	69655-05-6
ATC code	J05AF02
PubChem	CID 50599
DrugBank	APRD00240
ChemSpider	45864
UNII	K3GDH6OH08
KEGG	D00296
ChEBI	CHEBI:490877
ChEMBL	CHEMBL1460
NIAID ChemDB	AIDSNO:000004
Chemical data
Formula	C10H12N4O3
Mol. mass	236.227 g/mol
SMILES	eMolecules & PubChem
	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 ;
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　　[★]

英: didanosine,
同: ジデオキシイノシン dideoxyinosine ddI
商: ヴァイデックス Videx
関: 核酸系逆転写酵素阻害薬

「ジデオキシイノシン」

　　[★]

英: dideoxyinosine、ddI
関: ジダノシン

[Videxpi-0] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ VIDEX (didanosine): chewable/dispersible buffered tablets; buffered powder for oral solution; pediatric powder for oral solution. Product information (July 2000)

[dhhs-1] DHHS panel. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 4, 2006). (Available for download from AIDSInfo)

[2] ttp://hosted.ap.org/dynamic/stories/U/US_HIV_DRUG_LIVER_RISKS?SITE=KYB66&SECTION=HOME&TEMPLATE=DEFAULT

[Moyle-3] Moyle GJ. Use of viral resistance patterns to antiretroviral drugs in optimising selection of drug combinations and sequences. Drugs 1996;52:168-185

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dideoxyinosine