Abstract
Synopsis
Didanosine is a dideoxynucleoside analogue which undergoes intracellular conversion to the putative active triphosphate metabolite. The active metabolite appears to inhibit viral reverse tran-scriptase and terminate the proviral DNA, and produces virustatic inhibition of actively replicating human immunodeficiency virus (HIV) at clinically relevant concentrations.
In phase I studies didanosine had beneficial effects on various surrogate markers of clinical efficacy and also improved clinical manifestations of HIV infection, with a 21-month survival rate of 80% in patients with acquired immune deficiency syndrome (AIDS) and 93% in patients with AIDS-related complex (ARC) in I study. Didanosine also improved CD4+ cell counts in a phase II/III trial in patients previously treated with zidovudine, whereas cell counts declined in patients continuing zidovudine therapy. However, the effects of didanosine on clinical end-points (disease progression, survival, HIV encephalopathy) remain to be established. Peripheral neuropathy and pancreatitis are the predominant dose-limiting adverse events and didanosine therapy should be withdrawn in patients developing signs or symptoms of pancreatitis and during acute treatment of Pneumocystis carinii pneumonia. However, at currently recommended clinical dosages didanosine is generally well tolerated with minimal haematological toxicity.
Thus, in a therapeutic area with few treatment options, didanosine offers a welcome alternative for patients intolerant of, or resistant to, zidovudine. There are a number of clinical trials in progress evaluating didanosine alone or in combination with other antiviral agents, and these results are awaited with considerable interest.
Pharmacodynamic Properties
Didanosine is a dideoxynucleoside analogue which undergoes intracellular phosphorylation to the putative active metabolite 2’,3’-dideoxyadenosine 5’-triphosphate (ddATP). Didanosine inhibits replication of the human immunodeficiency virus (HIV), probably via inhibition of viral reverse transcriptase and termination of the proviral DNA chain by ddATP, but is not virucidal per se.
Didanosine has dose-proportional activity against HIV in a range of in vitro models, with approximately 100% inhibition of viral replication observed at drug concentrations which are both achievable in humans and not associated with significant in vitro cytotoxicity (≈ 20 μmol/ L). In contrast to zidovudine, didanosine had minimal effects on bone marrow progenitor cells at clinically relevant concentrations, and improved the viability and function of polymorpho-nuclear leucocytes from patients with HIV infection. In vitro synergism against HIV has been observed between didanosine and various other antiviral agents including zidovudine and riba-virin. Cross-resistance to didanosine has not been observed in zidovudine-resistant clinical isolates but a decrease in HIV sensitivity has been reported after prolonged didanosine therapy.
Pharmacokinetic Properties
The pharmacokinetic properties of didanosine have been studied in patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex (ARC). Didanosine is acid labile and in clinical trials, was usually given orally on an empty stomach, either in a citrate/phosphate buffer solution or immediately after antacid administration. Under these conditions didanosine in doses up to 10.2 mg/kg had an oral bioavailability of approximately 40%, although interpatient variation was extensive. The relationship between dose and maximum plasma didanosine concentration (Cmax) was linear in this dosage range, with a Cmax of 24 μmol/L occurring approximately 0.6 hours after didanosine 10.2 mg/kg orally. At higher oral dosages, bioavailability was reduced to approximately 20%, possibly because of incomplete absorption or a saturable absorption mechanism. A buffered chewable/dispersible tablet is also available and has approximately 20 to 25% increased bioavailability compared with other formulations. The area under the plasma didanosine concentration-time curve has been correlated with reductions in p24 antigen levels and neuropsychological improvement in patients.
The plasma half-life of didanosine is short (0.6 to 1.4 hours) but the putative active metabolite ddATP has an intracellular half-life of more than 12 hours. Steady-state volume of distribution is dose-independent and approximates the volume of total body water. Didanosine concentrations in the CSF were 21% of plasma concentrations 1 hour after an intravenous infusion but were detectable in only 3 CSF samples from 20 children receiving oral didanosine 20 to 180 mg/m2. Animal studies suggest concomitant probenecid may increase didanosine CSF penetration. Didanosine undergoes extensive metabolism to ddATP, uric acid and/or purine metabolites. Didanosine clearance was dose-independent and 35 to 60% of a dose was recovered unchanged in the urine, most within the first 8 hours.
The pharmacokinetic properties of didanosine are similar after single and multiple dose administration and appear comparable in adults, children and pregnant women. Didanosine crosses the placenta. Half-life was increased approximately 3-fold in patients with renal failure but didanosine was removed by dialysis, with the half-life approximating that in patients with normal renal function
Clinical Efficacy
In phase I studies didanosine had beneficial effects on surrogate markers of HIV infection which are considered to serve as indicators of clinical efficacy. CD4+ cell counts increased, the CD4+: CD8+ ratio improved and serum viral p24 antigen levels decreased. Constitutional symptoms (fatigue, anorexia, reduced energy) improved, with resolution of oral hairy leucoplakia and peripheral neuropathy, decreased organomegaly, improvements in other haematological parameters, and increased cognitive function observed in individual studies. 21-month survival rate was 80% in patients with AIDS and 93% in patients with ARC in 1 study. The results from these studies probably underestimate the efficacy of didanosine as most evaluated a large range of dosages, with little efficacy at the lowest dosages and marked toxicity at the highest dosages. Patients with ARC, receiving adequate therapeutic dosages of didanosine, and not previously treated with zidovudine, were more likely to respond.
Interim analysis of a phase II/III trial showed CD4+ cell counts were increased at weeks 12 and 24 in patients receiving didanosine 500 or 750 mg/day, whereas they decreased in patients receiving zidovudine 600 mg/day; however, these patients had previously received long term zidovudine therapy, which probably precluded any further significant response to this agent. Preliminary results indicate that combination of didanosine with zidovudine or interferon-α also improves surrogate markers of infection.
However, none of these studies have as yet provided adequate data on the effects of didanosine treatment on the primary clinical endpoints of HIV infection, that is, disease progression and patient survival.
Tolerability
The spectrum of adverse events associated with didanosine differs from that produced by zidovudine; in particular, didanosine haematological toxicity is minimal. In phase I trials, peripheral neuropathy and pancreatitis were the major dose-limiting adverse effects associated with didanosine therapy but both were relatively infrequent at dosages less than 13 mg/kg/day. Both usually resolved upon didanosine withdrawal and the drug was reintroduced at a lower dosage without recurrence in some patients. Pancreatitis was occasionally fatal (less than 0.35% incidence in more than 10 000 patients receiving didanosine in phase II trials or the expanded access programme) and the risk of developing pancreatitis appears to correlate with advanced HIV disease, previous history of pancreatitis, poor clinical status, and concomitant use of alcohol or medications also associated with pancreatitis. Dose-limiting hepatitis, seizures, retinal atrophy, heart failure, QT prolongation, optic neuritis, rash and hypocalcaemia have also been reported.
Other adverse events occurring in patients receiving didanosine have included haematological abnormalities, laboratory abnormalities, and mild nonspecific symptoms such as headache, dry mouth, insomnia, irritability and restlessness. However, it is difficult to attribute these to didanosine as HIV infection is associated with a variety of general symptoms and abnormalities. Diarrhoea and hypokalaemia were observed in some patients but were generally attributed to the buffer solution administered with didanosine.
Dosage and Administration
Didanosine is usually administered every 12 hours and should be taken on an empty stomach, either as the buffered tablets, concomitantly with a citrate/phosphate buffer solution (pH 7 to 8) or antacid solution, or immediately after an antacid dose, to reduce acid hydrolysis. Dosage is adjusted according to bodyweight in adults and body surface area in children. Dosage recmmendations are not available for children aged less than 6 months. In patients with renal failure, didanosine dosage should be reduced 2- to 3-fold and the drug administered at the end of haemo-dialysis. Dosage reduction should also be considered in patients with hepatic impairment. Drugs with absorption dependent on gastric acidity should be given at least 2 hours before didanosine. Didanosine should be used with extreme caution in patients with an increased risk of pancreatitis and should be withdrawn if signs and symptoms of pancreatitis develop and during acute treatment of Pneumocystis carinii pneumonia.
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Various sections of the manuscript reviewed by: E. De Clercq, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium; F.-D. Goebel, Medizinische Poliklinik der Universitat München, München, Federal Republic of Germany; C. Katlama, Groupe Hospitalier, Pitie-Salpetriere, Paris, France; J.S. Lambert, Infectious Disease Unit, University of Rochester Medical Center, Rochester, New York, USA; A. Matsuda, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan; B. Mueller, Pediatrics Branch, National Institutes of Health, National Cancer Institute, Bethesda, Maryland, USA; H. Mitsuya, Experimental Retrovirology Section, Medicine Branch, The Clinical Oncology Program, National Cancer Institute, Bethesda, Maryland, USA; H.C. Neu, Division of Infectious Diseases, College of Physicians and Surgeons of Columbia University, New York, New York, USA; A.J. Pinching, Department of Immunology, St Mary’s Hospital Medical School, London, England; PA. Pizzo, Pediatrics Branch, National Institutes of Health, National Cancer Institute, Bethesda, Maryland, USA; B. Rolinski, Medizinische Poliklinik der Universitat München, München, Federal Republic of Germany; E. Sandström, Department of Dermatology, Venhalsan, Södersjukhuset, Stockholm, Sweden; J.A. Vale, West Midlands Poisons Unit, Dudley Road Hospital, Birmingham, England; R. Yarchoan, Retroviral Diseases Section, National Cancer Institute, Bethesda, Maryland, USA.
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Faulds, D., Brogden, R.N. Didanosine. Drugs 44, 94–116 (1992). https://doi.org/10.2165/00003495-199244010-00008
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DOI: https://doi.org/10.2165/00003495-199244010-00008