Didanosine

Article Author:
Oleksandra Gerus
Article Editor:
Hoang Nguyen
Updated:
6/2/2020 6:38:36 PM
PubMed Link:
Didanosine

Indications

Didanosine, also is known as ddI, is a purine nucleoside analog reverse transcriptase inhibitor (NRTI) used in combination with antiretroviral regiments of anti-HIV therapy. After its uptake into a cell, it works by inhibiting the activity of HIV-1 reverse transcriptase. It is also effective as a monotherapy.[1] In several studies, the use of didanosine delayed progression of diseases in AIDS patients and increased both short- and long-term survival.[2]

Didanosine's primary use is in patients intolerant to zidovudine, abacavir, or tenofovir. The patients with the M184V mutation that are failing lamivudine therapy can switch to didanosine.[3] In patients with the M184V mutation, viral serum levels were significantly lower in comparison to the patients treated with HAART therapy without ddI.[4]

Didanosine therapy in children has shown potent in-vivo antiviral activity and delays in disease progression.[5] 

Mechanism of Action

Didanosine is a nucleoside analog that must first undergo conversion to its active form dideoxyadenosine-5'-triphosphate (ddATP). ddATP terminates viral DNA growth by inhibiting HIV reverse transcriptase. Multiple clinical trials showed a decrease in plasma HIV RNA levels while increasing CD4+ cell counts in previously untreated patients.[5]

Didanosine is an acid-liable drug with low bioavailability (20-40%). Due to being water-soluble and degraded in the GI tract into inactive hypoxanthine. To increase bioavailability, and remove the need for antacid administration, an encapsulated enteric-coated bead formula was developed.[6] Clinical studies showed a long half-life of an active metabolite, allowing it to be a once-daily dose.[7] 

Oral didanosine administration showed an impaired absorption of pH-dependent medications such as itraconazole, dapsone, and ketoconazole. The fetal concentration of didanosine was 20 to 50 percent of the mother's concentration. During the observation, concentration in the cerebrospinal fluid was low.[5] The drug is excreted through the kidneys; thus, dose modification should be a consideration in patients with kidney impairment. Co-administration with ciprofloxacin or tetracycline has shown to impair the absorption of didanosine due to the formation of insoluble chelates.[1]

Administration

Didanosine demonstrated as an effective monotherapy in both adults and children; however, to prevent drug resistance, combination therapy is preferred. Due to the reduction of bioavailability by 20 to 25% when administered with food,  it is recommended to administer the drug on an empty stomach 30 minutes before ingestion. Dosage, weight depended, is currently 200 mg for patients with body weight over 60 kg orally, twice daily.  In adults under 60kg of body weight, the dosage should be reduced to 125 mg, orally, twice daily.[5]

For adults, pediatric powder formulation requires administration with an antacid. The recommended dose, 120 mg twice daily with 12-hour intervals, should be adjusted in a patient with impaired kidney functions.[5][1]

  • Dual Combination Therapy with Nucleoside Reverse Transcriptase Inhibitor(NRTI)

The combination of zidovudine (200 mg, orally, three times a day) plus didanosine (200 mg, orally, twice daily) should be taken 30 minutes before ingestion.  

This combination therapy showed an increase in CD4 cells and a decrease in HIV-1 RNA serum concentrations compared to zidovudine monotherapy. Additionally, delays in AIDS-defining events were significantly prolonged.[8][9]

  • Triple Combination Therapy with Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI) and Nucleoside Reverse Transcriptase Inhibitors(NRTI)

This triple therapy consists of nevirapine (200 mg, orally, once daily first two weeks and then 200 mg, orally, twice daily ) plus zidovudine (200 mg, orally, three times a day) plus didanosine (200 mg, orally, twice daily for the patients with body weight over 60 kg). 

Patients on triple therapy had an 18% higher mean CD cell count compared to zidovudine and didanosine dual therapy. Severe rashes, however, were observed in patients receiving triple therapy.  For these patients, dual therapy is a preferable option.[10]

  •  Dual combination with DNA synthesis inhibitors. 

The combination dosage is as follows: hydroxyurea (500 mg orally, twice daily plus didanosine (200 mg, orally, twice daily). A combination of hydroxyurea and didanosine against HIV-1 has demonstrated the suppression of several resistant-prone strains.[11]

Adverse Effects

Common Adverse Reactions

  • Peripheral neuropathy
  • Pancreatitis
  • Portal hypertension
  • Lactic acidosis
  • Hepatitis
  • Optical neuritis
  • Hepatomegaly with steatosis
  • Hyperglycemia
  • Development of diabetes mellitus 
  • Hyperuricemia
  • Depression
  • Restlessness
  • Anxiety

Uncommon Severe Adverse Reactions

  • Diarrhea
  • Headache
  • Nausea
  • Rash 
  • Vomiting
  • Agitation
  • Dizziness

Contraindications

Ribavirin

This contraindication is due to increased mitochondrial toxicity observed in patients with co-administration of didanosine and treatment of Ribavirin, which led to severe metabolic acidosis syndrome.[12]

Stavudine

Didanosine co-administration has shown correlations with hepatoxicity, metabolic acidosis, and peripheral neuropathy.[13]

Allopurinol

Co-administration increased systemic exposure to didanosine by up to 300%.[14]

Pregnancy 

Didanosine use has shown correlations with the development of transplacental oncogenicity in children exposed to the drug in-utero.[15]

Monitoring

During treatment, all patients require monitoring for elevated pancreatic enzyme levels. If signs of drug-induced pancreatitis are present, the clinician should discontinue didanosine. Patients with advanced HIV infections are at an increased risk of developing pancreatitis and should not be placed on didanosine if they have a diagnosis of pancreatitis.[16] Lipase and isoamylase tests have demonstrated to be the most cost-saving and effective method of pancreatic damage in HIV patients.[17]

HIV- infected patients have an increased chance of developing acute kidney injuries, caused by both HIV-dependent and anti-retroviral administration.[18] Patients with signs of lactic acidosis, especially with preexisting renal insufficiency, should be monitored with a high degree of suspicion.[19] For patients with a low risk of kidney disease progression, an annual screen with eGFR, urinalysis, blood pressure, and lipid/glucose levels is recommended. Levels of eGFR in such patients should have monitoring for declines. For patients with an intermediate risk of kidney disease progression, the same tests, with considerations for a renal ultrasound, should be performed every six months. In a case of high risk for kidney disease progression, the patient should have all previously mentioned screenings performed every three months, including a renal ultrasound.[20]

Toxicity

Didanosine, a concentration-dependent drug at high doses, has been shown to inhibit the proliferation of bone marrow progenitor cells. Its myelosuppressive effect is reversible by the administration of erythropoietin.[5] Co-administration with tenofovir has correlations with didanosine overdose and hyperglycemia in underweight patients. This finding suggests taking caution when administering these drugs together to prevent serious complications, such as a diabetic coma.[21]   

Mitochondrial toxicity, induced by the inhibition of mitochondrial DNA polymerase due to ddI, can cause severe metabolic dysfunctions that are usually associated with inherited mitochondrial disease, most commonly presented as hepatic steatosis, lactic acidosis, and nephrotoxicity.[22]

Intra-ocular toxicity, which presented as peripheral chorioretinal atrophy from ddI administration, has been reported in children under age 2.[23]

Enhancing Healthcare Team Outcomes

The World Health Organization (WHO), 2015 guidelines recommended initiation antiretroviral therapy in all HIV positive patients. Studies have shown that early administration of antiretroviral therapy significantly decreased cost as well as adverse patient outcomes.[24]

When managing patients with existing comorbidities, it is essential to communicate with other clinicians for assistance. Collaboration between health care providers can decreases instances of developing life-threatening events. Due to the increased toxicity of didanosine, it is important to educate patients about signs of potentially life-threatening conditions associated with drug administration.


References

[1] Pollard RB, Didanosine once daily: potential for expanded use. AIDS (London, England). 2000 Nov 10;     [PubMed PMID: 11101051]
[2] Zidovudine, didanosine, and zalcitabine in the treatment of HIV infection: meta-analyses of the randomised evidence. HIV Trialists' Collaborative Group. Lancet (London, England). 1999 Jun 12;     [PubMed PMID: 10376616]
[3] Lange J, The power of simplicity. International journal of STD     [PubMed PMID: 14617399]
[4] Sproat M,Pozniak AL,Peeters M,Winters B,Hoetelmans R,Graham NM,Gazzard BG, The influence of the M184V mutation in HIV-1 reverse transcriptase on the virological outcome of highly active antiretroviral therapy regimens with or without didanosine. Antiviral therapy. 2005;     [PubMed PMID: 15865231]
[5] Perry CM,Balfour JA, Didanosine. An update on its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV disease. Drugs. 1996 Dec;     [PubMed PMID: 8957161]
[6] Damle BD,Kaul S,Behr D,Knupp C, Bioequivalence of two formulations of didanosine, encapsulated enteric-coated beads and buffered tablet, in healthy volunteers and HIV-infected subjects. Journal of clinical pharmacology. 2002 Jul;     [PubMed PMID: 12092746]
[7] Seremeta KP,Tur MI,Pérez SM,Höcht C,Taira C,López Hernández OD,Sosnik A, Spray-dried didanosine-loaded polymeric particles for enhanced oral bioavailability. Colloids and surfaces. B, Biointerfaces. 2014 Nov 1;     [PubMed PMID: 25444665]
[8] Schooley RT,Ramirez-Ronda C,Lange JM,Cooper DA,Lavelle J,Lefkowitz L,Moore M,Larder BA,St Clair M,Mulder JW,McKinnis R,Pennington KN,Harrigan PR,Kinghorn I,Steel H,Rooney JF, Virologic and immunologic benefits of initial combination therapy with zidovudine and zalcitabine or didanosine compared with zidovudine monotherapy. Wellcome Resistance Study Collaborative Group. The Journal of infectious diseases. 1996 Jun;     [PubMed PMID: 8648207]
[9] Saravolatz LD,Winslow DL,Collins G,Hodges JS,Pettinelli C,Stein DS,Markowitz N,Reves R,Loveless MO,Crane L,Thompson M,Abrams D, Zidovudine alone or in combination with didanosine or zalcitabine in HIV-infected patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter. Investigators for the Terry Beirn Community Programs for Clinical Research on AIDS. The New England journal of medicine. 1996 Oct 10;     [PubMed PMID: 8813040]
[10] D'Aquila RT,Hughes MD,Johnson VA,Fischl MA,Sommadossi JP,Liou SH,Timpone J,Myers M,Basgoz N,Niu M,Hirsch MS, Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Annals of internal medicine. 1996 Jun 15;     [PubMed PMID: 8633815]
[11] Foli A,Lori F,Maserati R,Tinelli C,Minoli L,Lisziewicz J, Hydroxyurea and didanosine is a more potent combination than hydroxyurea and zidovudine. Antiviral therapy. 1997 Jan;     [PubMed PMID: 11322264]
[12] Butt AA, Fatal lactic acidosis and pancreatitis associated with ribavirin and didanosine therapy. The AIDS reader. 2003 Jul;     [PubMed PMID: 12889452]
[13] Vogel M,Rockstroh JK, Hepatotoxicity and liver disease in the context of HIV therapy. Current opinion in HIV and AIDS. 2007 Jul;     [PubMed PMID: 19372904]
[14] Ray AS,Olson L,Fridland A, Role of purine nucleoside phosphorylase in interactions between 2',3'-dideoxyinosine and allopurinol, ganciclovir, or tenofovir. Antimicrobial agents and chemotherapy. 2004 Apr;     [PubMed PMID: 15047506]
[15] Hleyhel M,Goujon S,Delteil C,Vasiljevic A,Luzi S,Stephan JL,Reliquet V,Jannier S,Tubiana R,Dollfus C,Faye A,Mandelbrot L,Clavel J,Warszawski J,Blanche S, Risk of cancer in children exposed to didanosine in utero. AIDS (London, England). 2016 May 15;     [PubMed PMID: 26854809]
[16] Blanchard JN,Wohlfeiler M,Canas A,King K,Lonergan JT, Pancreatitis with didanosine and tenofovir disoproxil fumarate [corrected]. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2003 Sep 1;     [PubMed PMID: 12942419]
[17] Tradati FC,Gringeri A,Santagostino E,Cultraro D,Simoni L,De Fazio C,Mezzi G,Cappelletti M,Malesci A,Mannucci PM, Prevalence of pancreatic disorders in HIV-infected hemophiliacs: diagnostic methods and their clinical significance. Biomedicine     [PubMed PMID: 7919111]
[18] Gameiro J,Agapito Fonseca J,Jorge S,Lopes JA, Acute kidney injury in HIV-infected patients: a critical review. HIV medicine. 2019 Feb;     [PubMed PMID: 30411475]
[19] Murphy MD,O'Hearn M,Chou S, Fatal lactic acidosis and acute renal failure after addition of tenofovir to an antiretroviral regimen containing didanosine. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2003 Apr 15;     [PubMed PMID: 12684925]
[20] Yombi JC,Jones R,Pozniak A,Hougardy JM,Post FA, Monitoring of kidney function in HIV-positive patients. HIV medicine. 2015 Sep;     [PubMed PMID: 25944246]
[21] García-Benayas T,Rendón AL,Rodríguez-Novóa S,Barrios A,Maida I,Blanco F,Barreiro P,Rivas P,González-Lahoz J,Soriano V, Higher risk of hyperglycemia in HIV-infected patients treated with didanosine plus tenofovir. AIDS research and human retroviruses. 2006 Apr;     [PubMed PMID: 16623636]
[22] Kakuda TN, Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clinical therapeutics. 2000 Jun;     [PubMed PMID: 10929917]
[23] Whitcup SM,Butler KM,Caruso R,de Smet MD,Rubin B,Husson RN,Lopez JS,Belfort R Jr,Pizzo PA,Nussenblatt RB, Retinal toxicity in human immunodeficiency virus-infected children treated with 2',3'-dideoxyinosine. American journal of ophthalmology. 1992 Jan 15;     [PubMed PMID: 1728133]
[24] Kuznik A,Iliyasu G,Habib AG,Musa BM,Kambugu A,Lamorde M, Initiation of antiretroviral therapy based on the 2015 WHO guidelines. AIDS (London, England). 2016 Nov 28;     [PubMed PMID: 27662547]