Medical Pharmacology Chapter 36:  Antiviral Drugs

• Antiretroviral Drugs Used in Treating HIV Infection

  • →Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (continued):

    • Didanosine (Videx)1

      • Didanosine (Videx, ddI) is an analog of deoxyadenosine.⁷ 

        • The drug structure below allows comparison with adenosine.

          • Structural Comparison between Adenosine (top), Didanosine (Videx) (Bottom)⁶

      • The drug shows antiretroviral activity against both HIV-one and HIV-two as well as against other retroviruses including HTLV-1.

        • (1) Didanosine enters the cell utilizing a nucleobase carrier transport system and is initially phosphorylated by 5'-nucleotidase and inosine 5'-monophosphate transferase.

        • (2) At this point, didanosine 5'-monophosphate is phosphorylated twice more in reactions catalyzed by adenylate kinase and phosphoribosyl pyrophosphate synthase,  resulting in formation of dideoxyadenosine 5’-diphosphate.

        • (3) The last step involves conversion of the diphosphate form to the triphosphate structure by reactions catalyzed by a cellular kinase and phosphoribosyl pyrophosphate synthase.

          • Accordingly, didanosine is a "prodrug", requiring three phosphorylation steps for activation.

             

            • Conversion of the "prodrug" Didanosine to Dideoxyadenosine-5'-triphosphate, the active drug form¹⁰

              Perry CM Noble S Didanosine:  An Updated Review of its Use in HIV Infection Drugs 58(6):  1099-1135, Dec 1999 Attribution:  The above figure is slight modification of Figure 1 in the reference above (10)  http://www.ncbi.nlm.nih.gov/pubmed/10651392

          • Dideoxyadenosine 5'-triphosphate, the active form, is an antiretroviral adenosine analog and the incorporation of which prevents elongation of proviral DNA.

            • Chain termination occurs as a consequence of adding the adenosine analog into the newly forming HIV DNA, in a reaction catalyzed by reverse transcriptase.

              • Absence of the 3'-hydroxyl group, as noted in the structure above, is sufficient to terminate chain elongation.

      • Mutations and Resistance to Didanosine (Videx): 

        • Resistance to the action of didanosine as a result of mutations in the retroviral reverse transcriptase enzyme is focused on codon (amino acid) 65 and 74.⁸ 

          • At position 65 the naturally occurring amino acid lysine is substituted by either arginine, glutamate or asparagine.

          • At position 74 the naturally occurring amino acid leucine is substituted by a valine.⁸  

            • The mutation at codon 74 reduces didanosine susceptibility (efficacy) by 5-25-fold as determined by in vitro assay.¹  

              • Patients failing to respond to didanosine may well exhibit this mutation.

        • Didanosine resistance may be influenced by other nucleoside analogue mutations.¹  

          • Furthermore, antiretroviral reverse transcriptase insertion mutations at codon 69 induce a cross-resistance to contemporary nucleoside analog drugs, including didanosine.¹

      • Pharmacokinetics:

        • Didanosine has an oral bioavailability of about 40%.⁷ 

          • The relatively low bioavailability associated with didanosine may be partially due to inactivation by purine nucleoside phosphorylase which catalyzes conversion of didanosine the hypoxanthine, ultimately converted to uric acid.¹

          • The agent is typically administered in the delayed release enteric-coated formulation to dosing being weight-based.⁶ 

            • Chewable tablets are buffered by calcium carbonate in magnesium hydroxide.¹  

              • By contrast, the powdered formulation uses citrate-phosphate buffer.

                • For the pediatric powder formulation, the buffer is omitted from the powder but when reconstituted with water,  mixing with a liquid and acid is performed.¹

          • Empty stomach administration of  didanosine is preferable, with the drug optimally taken 30 min. before or two hours after a meal.^6,7 

            • One challenge associated with empty-stomach didanosine administration is that some antiretroviral drugs which might be administered along with didanosine in combination treatment (such as most protease inhibitors ) must be given with food.¹

            • Buffered formulations allow the drug to avoid gastric acid inactivation.⁷ 

              • The buffer used in didanosine tablets however interfere with absorption of other drugs including indinavir, delavirdine, atazanavir (antiretrovirals) as well as dapsone, itraconozole, and fluoroquinolones.⁷   

                • As a consequence, administration of didanosine and these agents should be at different times.

          • Didanosine serum levels have been shown to be increased when didanosine is administered along with antiviral agents tenofovir or ganciclovir.⁷ 

            • By contrast, didanosine serum levels may be decreased by atazanavir, ritonovir, tipranavir  (antiretrovirals) as well as by methadone.

          • Didanosine should not be used along with ribavirin.⁷   

          • Didanosine excretion occurs by both glomerular filtration and by tubular secretion.¹  

            • Didanosine metabolism occurs only to a very limited extent.

          • With renal insufficiency, didanosine dosing should be reduced in accord with creatinine clearance.⁶ 

      • Adverse Effects:

        • The major toxicity associated with didanosine administration is pancreatitis, occurring with the frequency of about 1-7%.¹² 

          • Risk factors for pancreatitis are numerous, including alcohol abuse and hypertriglyceridemia, which describe relative didanosine contraindications.⁷

            • Avoidance of other drugs, the administration which may result in pancreatitis, such as zalcitabine, ribavirin, stavudine and hydroxyurea is appropriate if didanosine administration is needed.

          • Another side effect, peripheral distal sensory neuropathy associated with didanosine administration is more likely to occur if didanosine is used along with stavudine, ribavirin, vincristine or isoniazid.⁷

            • Early clinical trial data suggest that didanosine-induced peripheral neuropathy is associated with about a 20% likelihood of occurrence.¹

              • Factors predisposing to peripheral neuropathy include higher dose didanosine and the presence of underlying HIV-related neuropathy and lower CD4⁺ T cell counts.¹  

              • This distal sensory neuropathy has been described as symmetrical, beginning in the feet and lower extremities.¹

                • Patients describe pain, numbness, and tingling in the affected limbs.

                • Discontinuation of didanosine early, just after symptoms are reported, will likely stabilize the neuropathy. 

                  • Under these circumstances the neuropathy is likely to improve or resolve. Unfortunately, extended didanosine use may result in an irreversible neuropathy.¹

            • Both peripheral neuropathy and pancreatitis may be due to didanosine-related mitochondrial toxicity.¹

          • In addition to pancreatitis and peripheral neuropathy, other severe adverse side effects include lactic acidosis and steatohepatitis.⁷  

            • A number of other side effects associated with didanosine have been described, including diarrhea, esophageal ulceration, cardiomyopathy, hepatitis, headache, irritability, insomnia and hypertriglyceridemia.

            • Didanosine administration may also induce gout attacks in susceptible patients who previously were hyperuricemic, albeit asymptomatic.

            • High-dose didanosine administration in adults and children may be associated with retinal abnormalities and optic neuritis.

              • This possibility is the basis for recommending retinal examinations.

            • Lipoatrophy appears to be more frequently noted in patients receiving didanosine or other thymidine antiretroviral chain termination analogues.⁷

           

      • Therapeutics

        • Didanosine Formulation Examples

          • Didanosine administration has been approved (FDA) as an antiretroviral for administration to adults and children infected with HIV when didanosine is given in combination with other antiretroviral drugs.¹   

            • Didanosine effectiveness has been demonstrated when it is combined with nucleoside analogues, antiretroviral protease inhibitors or non-nucleoside reverse transcriptase inhibitors.¹ 

          • However, didanosine  may not be a drug of choice given availability of alternative antiretrovirals in some circumstances.⁹  

            • For example didanosine plus lamivudine is not recommended as initial therapy because of:⁹

              • Inferior antiviral efficacy

              • Didanosine toxicities (as described above) and

              • Limited clinical trial data in antiretroviral-naïve individuals.⁹  

            • The combination of didanosine and tenofovir disoproxil fumarate is similarly not recommended as initial therapy due to:⁹

              • High rates of virologic failure early in therapy

              • Rapid development of drug-resistant mutations

              • Potential for immunologic nonresponse manifesting as CD4⁺ T cell count reduction and adverse effects due to didanosine itself.⁹ 

          • With respect to didanosine as monotherapy: ⁹

            • Single-nucleoside reverse transcriptase inhibitor treatment is not recommended, since this approach does not result in potent and sustained antiretroviral activity.⁹  

            • To prevent mother-to-child transmission, zidovudine (AZT), although not recommended might be used in special circumstances in women with HIV RNA <1000 copies/cc, although a potent combination protocol would be preferred.

            • Dual (two drug) nucleoside reverse transcriptase inhibitors are not recommended  because they have not been shown to provide potent as well sustained antiretroviral activity when compared to triple-drug combination treatments.

            • Triple-non-nucleoside reverse transcriptase antiretroviral protocols other than abacavir + lamivudine + zidovudine and possibly lamivudine + zidovudine + tenofovir should not be used as a result of either suboptimal antiretroviral activity or lack of sufficient clinical data.⁹

          • Didanosine plus stavudine as an example of a dual-nucleoside reverse transcriptase inhibitor backbone is not recommended due to toxicities, especially peripheral neuropathy, pancreatitis as well as lactic acidosis.⁹  

            • This combination may have been responsible for deaths of several HIV- infected pregnant women, secondary to significant lactic acidosis with or without hepatic steatosis and pancreatitis.

          • Didanosine + tenofovir in combination may increase didanosine concentrations resulting in increased incidence of serious didanosine-related toxicities such as pancreatitis and lactic acidosis.⁹  

            • This combination may also be associated with immunologic nonresponse or absence of CD4⁺ cell reduction despite viral suppression.

            • Also, this combination has been associated with early virologic failure as well as rapid development of resistance mutations. Consequently, this combination is generally not recommended.⁹