Relationship between Didanosine Exposure and Surrogate Marker Response in Human Immunodeficiency Virus-Infected Outpatients

In 1991 didanosine became the second nucleoside analog to gain Food and Drug Administration approval for the treatment of human immunodeficiency virus (HIV) infection. Minimal hematologic toxicity and notable in vitro activity against zidovudine-resistant strains of HIV made didanosine an attractive alternative for patients who were intolerant of zidovudine or who were experiencing clinical or immunologic deterioration during zidovudine therapy. Early phase I trials with didanosine demonstrated potentially beneficial changes in weight, CD4 cell count, p24 antigen levels, and clinical signs or symptoms (2, 28). The pharmacokinetics of didanosine have been studied in patients with AIDS and severe AIDS-related complex (14, 15, 17–20, 24, 31). Didanosine exhibits linear pharmacokinetic behavior after the administration of oral doses of 0.8 to 10.2 mg/kg of body weight. The elimination half-life after oral administration is approximately 1.4 h, with renal clearance accounting for up to 50% of total body clearance. Renal clearance values exceed the glomerular filtration rate, indicating renal tubular secretion. The intracellular half-life of the active form (2′,3′-dideoxyadenosine-5′-triphosphate; ddATP) of didanosine is at least 12 h (1), allowing for twice-daily dosing. The bioavailability of didanosine, an acid-labile drug, differs among the formulations studied and exhibits significant inter- and intrapatient variability. Potential relationships between didanosine exposure and surrogate markers of antiretroviral efficacy have been investigated. Beltangady and coworkers (7) evaluated the relations between the average steady-state concentration in plasma (Cpss) of didanosine and CD4 cell counts, p24 antigenemia, and weight gain in patients with AIDS or severe AIDS-related complex participating in a phase I study. Median didanosine Cpss values among patients having favorable responses in CD4 cell counts, p24 antigenemia, and weight gain at week 12 of therapy were significantly higher than those among patients without such improvements. After corrections for baseline CD4 cell counts and prior zidovudine history with the use of a logistic regression model, didanosine Cpss values remained positively correlated with improvements in the surrogate markers studied. Drusano et al. (11), in an earlier analysis of phase I data, defined didanosine exposure in terms of the steady-state area under the concentration-versus-time curve (AUC) when evaluating its relationship to average CD4 cell counts and p24 antigen concentrations during therapy. Increases in CD4 cell counts were determined to be independent of didanosine exposure and proportional to the baseline CD4 cell count. A reduction in circulating p24 antigen levels, however, was found to be related to both the single-dose and the cumulative didanosine AUC. Indeed, an increasing cumulative didanosine AUC appeared to be highly correlated with p24 antigen suppression. The purpose of this investigation was to examine the feasibility of using observational data in a clinic setting to determine didanosine exposure and to further evaluate the relationship between didanosine exposure (defined as the cumulative didanosine AUC) and surrogate marker response in a group of HIV-infected outpatients.