Didanosine

Didanosine is a synthetic nucleoside analogue of the naturally occurring nucleoside deoxyadenosine in which the 3'-hydroxyl group is replaced by hydrogen. Intracellularly, didanosine is converted by cellular enzymes to the active metabolite, dideoxyadenosine 5'-triphosphate. Dideoxyadenosine 5'-triphosphate inhibits the activity of HIV-1 reverse transcriptase both by competing with the natural substrate, deoxyadenosine 5'-triphosphate, and by its incorporation into viral DNA causing termination of viral DNA chain elongation.

In Vitro HIV Susceptibility

The in vitro anti-HIV-1 activity of didanosine was evaluated in a variety of HIV-1 infected lymphoblastic cell lines and monocyte/macrophage cell cultures. The concentration of drug necessary to inhibit viral replication by 50% (IC₅₀) ranged from 2.5 to 10 µM (1 µM = 0.24 µg/mL) in lymphoblastic cell lines and 0.01 to 0.1 µM in monocyte/macrophage cell cultures. The relationship between in vitro susceptibility of HIV to didanosine and the inhibition of HIV replication in humans has not been established.

Drug Resistance

HIV-1 isolates with reduced sensitivity to didanosine have been selected in vitro and were also obtained from patients treated with didanosine. Genetic analysis of isolates from didanosine-treated patients showed mutations in the reverse transcriptase gene that resulted in the amino acid substitutions K65R, L74V, and M184V. The L74V mutation was most frequently observed in clinical isolates. Phenotypic analysis of HIV-1 isolates from 60 patients (some with prior zidovudine treatment) receiving 6 to 24 months of didanosine monotherapy showed that isolates from 10 of 60 patients exhibited an average of a 10-fold decrease in susceptibility to didanosine in vitro compared to baseline isolates. Clinical isolates that exhibited a decrease in didanosine susceptibility harbored one or more didanosine-associated mutations. The clinical relevance of genotypic and phenotypic changes associated with didanosine therapy has not been established.

Cross-resistance

HIV-1 isolates from 2 of 39 patients receiving combination therapy for up to 2 years with zidovudine and didanosine exhibited decreased susceptibility to zidovudine, didanosine, zalcitabine, stavudine, and lamivudine in vitro. These isolates harbored five mutations (A62V, V75I, F77L, F116Y, and Q151M) in the reverse transcriptase gene. The clinical relevance of these observations has not been established.

The pharmacokinetic parameters of didanosine are summarized in Table 1. Didanosine is rapidly absorbed, with peak plasma concentrations generally observed from 0.25 to 1.50 hours following oral dosing. Increases in plasma didanosine concentrations were dose proportional over the range of 50-400 mg. Steady-state pharmacokinetic parameters did not differ significantly from values obtained after a single dose. Binding of didanosine to plasma proteins in vitro was low (<5%). Based on data from in vitro and animal studies, it is presumed that the metabolism of didanosine in man occurs by the same pathways responsible for the elimination of endogenous purines.

Table 1. Mean ± SD Pharmacokinetic Parameters for Didanosine in Adult and Pediatric Patients:

CSF = cerebrospinal fluid
^a following IV administration
^b following IV administration in adults and IV or oral administration in pediatric patients
^c mean ± SE
^d following oral administration

Effect of Food on Absorption of Didanosine

Didanosine peak plasma concentrations (C_max) and area under the plasma concentration time curve (AUC) were decreased by approximately 55% when didanosine tablets were administered up to 2 hours after a meal. Administration of didanosine tablets up to 30 minutes before a meal did not result in any significant changes in bioavailability. Didanosine should be taken on an empty stomach, at least 30 minutes before or 2 hours after eating.

Special Populations

Renal Insufficiency

It is recommended that the didanosine dose be modified in patients with reduced creatinine clearance and in patients receiving maintenance hemodialysis. Data from two studies indicated that the apparent oral clearance of didanosine decreased and the terminal elimination half-life increased as creatinine clearance decreased (see Table 2). Following oral administration, didanosine was not detectable in peritoneal dialysate fluid (n=6); recovery in hemodialysate (n=5) ranged from 0.6% to 7.4% of the dose over a 3-4 hour dialysis period. The absolute bioavailability of didanosine was not affected in patients requiring dialysis.

Table 2. Mean ± SD Pharmacokinetic Parameters for Didanosine Following a Single Oral Dose:

|_. \5<>_.Creatinine Clearance (mL/min)

^a ND = not determined due to anuria
CL_cr = creatinine clearance
CL/F = apparent oral clearance
CL_R = renal clearance

Pediatric Patients

The pharmacokinetics of didanosine have been evaluated in HIV-infected pediatric patients from 0.7 to 18.9 years of age (see Table 1). Overall, the pharmacokinetics of didanosine in pediatric patients greater than 0.7 years of age are similar to those of didanosine in adults. Didanosine plasma concentrations increased in proportion to oral doses ranging from 80 to 180 mg/m².

Geriatric Patients

Didanosine pharmacokinetics have not been studied in patients over 65 years of age.

Gender

The effects of gender on didanosine pharmacokinetics have not been studied.

Drug Interactions

Drug interaction studies have demonstrated that there are no clinically significant pharmacokinetic interactions between didanosine and the following: dapsone, loperamide, metoclopramide, nevirapine, ranitidine, rifabutin, ritonavir, stavudine, sulfamethoxazole, trimethoprim, and zidovudine. Studies with dapsone, nevirapine, rifabutin, ritonavir, stavudine, and zidovudine were multipledose studies. Studies with loperamide, metoclopramide, ranitidine, sulfamethoxazole, and trimethoprim were single-dose studies, and effects on pharmacokinetics at steadystate are not known.

Animal Toxicology

Evidence of a dose-limiting skeletal muscle toxicity has been observed in mice and rats (but not in dogs) following long-term (greater than 90 days) dosing with didanosine at doses that were approximately 1.2 to 12 times the estimated human exposure. The relationship of this finding to the potential of didanosine to cause myopathy in humans is unclear. However, human myopathy has been associated with administration of didanosine and other nucleoside analogues.