RELATION BETWEEN PLASMA-CONCENTRATIONS OF DIDANOSINE AND MARKERS OF ANTIVIRAL EFFICACY IN ADULTS WITH AIDS OR AIDS-RELATED COMPLEX

The relation between the average steady-state plasma concentration (Cp(SS)) of didanosine and selected measures of efficacy, such as CD4 cell count, p24 antigenemia, and weight gain, was evaluated in patients participating in a phase 1 safety and pharmacokinetics study. All patients were diagnosed as having AIDS or severe AIDS-related complex. These individuals first received intravenous didanosine for 2 weeks at doses of 0.8-33 mg/(kg.d) and then took the drug orally at twice the intravenous dose. Cp(SS) values were calculated on the basis of apparent oral clearance after 4 weeks of oral administration and average daily dose over the first 12 weeks of the study. These data were available for 61 patients enrolled at three clinical sites. High values for Cp(SS) were strongly correlated with an increase in CD4 count (P = .006), a decrease in serum levels of p24 antigen (P = .006), and weight gain (P = .0001) at week 12. Logistic regression analysis was used to assess the influence of Cp(SS) on response (as judged by the three criteria just mentioned) after adjustment for other potential factors related to infection with human immunodeficiency virus. The baseline CD4 cell count and the status with regard to prior zidovudine therapy were related to the CD4 response. However, the odds that a response would include all three parameters were nearly twice as high when the Cp(SS) value increased by twofold. These results demonstrate that the Cp(SS) value, which may be a better measure of the exposure of an individual patient to a drug than the weight-normalized dose, is positively correlated with improvements in parameters used to evaluate the antiviral activity of didanosine.