Didanosine : An Update on its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy in the Management of HIV Disease.

SYNOPSIS: Didanosine is a dideoxynucleoside analogue, which is phosphorylated to the active metabolite dideoxyadenosine triphosphate (ddATP) intracellularly. At therapeutic concentrations, ddATP inhibits HIV replication by inhibiting HIV reverse transcriptase. Didanosine is established as a first-line treatment for patients with HIV disease and has recently been shown to be superior to zidovudine monotherapy in the treatment of patients with intermediate-stage HIV infection. In clinical practice, however, combination regimens of antiretroviral drugs are generally considered preferable to monotherapy as first-line treatment for most patients with HIV disease. Importantly, 2 large multicentre studies have demonstrated that combination therapy with didanosine and zidovudine was more effective than zidovudine monotherapy in delaying disease progression and death in patients with intermediate or advanced HIV disease. In other comparative studies, improvements in surrogate markers of HIV disease were generally greater in patients who received combination therapy than in recipients of antiretroviral drug monotherapy. Improvements in surrogate markers were also observed in children who received didanosine monotherapy in several clinical trials. Although the efficacy of combination antiretroviral drug therapy has not yet been investigated extensively in children, a combination regimen of didanosine and zidovudine was well tolerated and achieved beneficial effects on surrogate markers of HIV disease. In addition, preliminary findings of a larger study have shown that disease progression was delayed in children and adolescents who received didanosine plus zidovudine combination therapy compared with those receiving zidovudine monotherapy. Didanosine has a tolerability profile that is distinctly different from that of zidovudine. In particular, didanosine exhibits only minimal haematological toxicity when administered either as a single agent or in combination with zidovudine. The most serious dose-limiting adverse effects associated with didanosine treatment are peripheral neuropathy and pancreatitis. In conclusion, didanosine monotherapy is an effective treatment for HIV infection. However, combination antiretroviral therapy is the optimal treatment strategy for most patients, and didanosine is now firmly established as a component of combination antiretroviral drug regimens for the first-line treatment of patients with HIV disease.

PHARMACODYNAMIC PROPERTIES: Didanosine is phosphorylated by intracellular enzymes to the active antiviral compound, 2',3'-dideoxyadenosine 5'-triphosphate (ddATP). ddATP prevents HIV replication by inhibiting the viral reverse transcriptase enzyme and terminating pro viral DNA chain elongation. Didanosine shows concentration-dependent antiviral activity in in vitro models of HIV infection and synergistic or additive activity has been observed with combinations of didanosine and other antiretroviral agents. At high concentrations, didanosine has inhibitory effects on bone marrow progenitor cells, which may be reversed in the presence of erythropoietin. Early erythroid progenitor cells are more sensitive to didanosine than later ery-throid progenitor and myeloid progenitor cells. A series of mutations at codons 74, 184 and/or 65 of the HIV pol gene that encodes the reverse transcriptase enzyme has been documented as a cause of viral resistance to didanosine.

PHARMACOKINETIC PROPERTIES: The pharmacokinetics of didanosine are similar in adults and children with HIV infection. The N-glycosidic bond in didanosine is acid labile; thus, to avoid degradation in the acidic conditions of the stomach, oral didanosine is formulated as a citrate/phosphate buffered powder for reconstitution with water and as a chewable/dispersible tablet containing antacids. After multiple doses of various formulations of oral didanosine (125 to 375mg twice daily) to fasted patients, maximum plasma concentrations (Cmax) of the drug ranged from 0.52 to 2.79 mg/L. There appears to be a linear relationship between the dose of didanosine and Cmax. The distribution of didanosine at steady-state (54L in adults and 9 to 40 L/m(2) in children with HIV infection) is dose-independent and approximately equal to the volume of total body fluid. Didanosine concentrations in placental and fetal circulations were 20 to 50% of maternal circulation concentrations. The drug crosses the blood-brain barrier, but concentrations of didanosine in cerebrospinal fluid are low. Didanosine is extensively metabolised to ddATP, to uric acid or enters the purine metabolic pool. The plasma elimination half-life of didanosine is relatively short, but the intracellular half-life of the putative metabolite ddATP is 8 to 40 hours. Approximately 30 to 60% of an oral or intravenous dose of didanosine was recovered unchanged in the urine within 8 hours of administration. In patients with AIDS and severe renal impairment [creatinine clearance of <0.12 L/h/1.73m(2) (<2 ml/min/1.73m )] total body clearance of didanosine was reduced by 75%.

THERAPEUTIC EFFICACY: The efficacy of didanosine as a first-line treatment for patients with HIV disease is now well established. In addition, didanosine has proved to be a useful alternative to zidovudine for patients who are intolerant of, or no longer responsive to, zidovudine. Recent results from the AIDS Clinical Trial Group (ACTG) protocol 175 trial indicated that didanosine monotherapy was significantly more effective than zidovudine in preventing progression to AIDS or death, or death alone, in both antiretroviral drug-experienced and -naive patients with intermediate-stage HIV infection. Didanosine is also firmly established as a component of antiretroviral combination therapy, which is now preferred to monotherapy as the first-line treatment strategy for most patients with HIV infection. Results of 2 large combination treatment trials (ACTG 175 and the Delta trial) in patients with intermediate or advanced HIV infection, indicated that recipients of didanosine plus zidovudine had a significant survival advantage over zidovudine monotherapy recipients. These findings have been supported by results of the Community Programs for Clinical Research on AIDS (CPCRA) 007 trial. In other comparative studies of didanosine, improvements in surrogate markers of HIV disease were generally greater in patients who received combination therapy than in recipients of antiretroviral drug monotherapy. Didanosine therapy has also been shown to improve surrogate markers of HIV disease in children. In addition, preliminary results of the ACTG 152 trial have shown a delay in disease progression in children who received didanosine mono-therapy or didanosine in combination with zidovudine, compared with children who received zidovudine alone. There are no published data available on the therapeutic efficacy of didanosine in pregnant women, but studies of the drug in pregnancy are in progress. Whether didanosine, like zidovudine, reduces the risk of vertical HIV transmission to the fetus or newborn infant is yet to be determined.

TOLERABILITY: The most serious dose-limiting adverse effects observed during didanosine treatment were peripheral neuropathy and pancreatitis, which were reported as adverse events in 16 and 5%, respectively, of 7806 patients with advanced disease who received the drug in the didanosine Expanded Access Program. However, a lower incidence of pancreatitis has been reported in patients with less advanced disease. In the ACTG 175 trial, the incidence of pancreatitis was 0.5% for the entire study population and there was an equal distribution of patients affected among the different treatment groups. Hyperuricaemia, reversible hyperglycaemia and development of diabetes mellitus have also been reported during treatment with the drug. Didanosine has a distinctly different tolerability profile to that of zidovudine. Notably, in contrast to zidovudine, didanosine, administered as monotherapy or in combination with zidovudine, is associated with minimal haematological toxicity. Other adverse events reported in patients who received the drug in the didanosine Expanded Access Program included diarrhoea (generally attributed to the citrate/phosphate buffer in the powder formulation), nausea and vomiting, headache, anxiety, dizziness, agitation and depression.

DRUG INTERACTIONS: Several clinically important drug interactions between oral formulations of didanosine (with gastric acid neutralising capacity) and other drugs have been reported. Most interactions resulted in impaired absorption of the coadministered agent (for example, itraconazole, ketoconazole and dapsone) and occurred as a result of the increase in gastric pH produced by oral didanosine. In addition, tetracycline and ciprofloxacin have impaired absorption when coadministered with the didanosine tablet formulation because of insoluble chelate formation. Few studies have demonstrated any clinically significant effects of concomitant medication on the pharmacokinetics of didanosine. However, concomitant administration of didanosine and ganciclovir resulted in a significant increase in mean didanosine Cmax and area under the plasma concentration-time curve values. This interaction may be of clinical significance and requires further study.

DOSAGE AND ADMINISTRATION: The dosage of didanosine in adults is determined by the body weight of the patient. Dosage also varies according to the didanosine formulation used, as bioavailability of the drug from the tablet is greater than from the citrate/phosphate buffer solution. For adults of ≥60kg bodyweight, recommended dosages of didanosine are 200mg (tablet) or 250mg (citrate/phosphate buffer solution) twice daily. For adults of ≤60kg bodyweight, dosages are 125mg (tablet) or 167mg (citrate/phosphate buffer solution) twice daily. Didanosine is also available in a paediatric powder formulation, which should be administered with an antacid. The recommended maintenance dosage of didanosine in children is 120mg/m(2) administered twice daily at 12-hour intervals. The dosage of didanosine should be reduced in patients with renal impairment [creatinine clearance 3.6 L/h (≤60 ml/min)], although data are insufficient at present to recommend specific dosages in this patient group. It is recommended that didanosine is administered on an empty stomach 30 minutes before a meal.