Background:  Didanosine (ddI) is a potent nucleoside reverse transcriptase inhibitor used for HIV infection treatment. A once daily administration of chewable / dispersible ddI tablets (Videx^®) was available for children in Burkina Faso but few pharmacokinetic data were reported with these galenic form and administration scheme. This study is part of a phase II trial on once-a-day pediatric HAART. The objectives were to describe ddI pharmacokinetics and to establish relationships between doses, plasma concentrations and treatment efficacy in children.

Methods:  ddI concentrations were measured in 40 children after 2 weeks and in 9 children after 2 to 5 months of ddI/lamivudine/efavirenz combination. A total of 166 ddI plasma samples were measured using an high-performance liquid chromatography (HPLC) assay with detection by ultraviolet absorbance. A population pharmacokinetic model was developed with NONMEM. The link between maximal concentration (C_max), area under the curve (AUC) and the decrease in HIV-1 RNA levels after 12 months of treatment was evaluated. The threshold AUC and C_max improving efficacy were determined and an optimized dosing schedule was simulated.

Results:  ddI pharmacokinetics was best described by a 1-compartment model with first order absorption and elimination. Mean population pharmacokinetic estimates with the corresponding inter-subject variabilities (%) were:  apparent elimination clearance CL/F = 146 L/h (90%) and apparent volume of distribution V/F = 356 L (122%). CL/F and V/F were increased, probably due to a lower bioavailability with tablets than with pediatric powder. Clearance increased with body surface area. The decrease in viral load after 12 months of treatment was significantly correlated with ddI AUC and C_max (p ≤0.02) during the first weeks of treatment. An AUC >0.85 mg/L.h was significantly linked to better viral load decrease (3 vs 2.4 log₁₀ copies/ml, p <0.03) and higher percentage of children with undetectable viral load after 1 year of treatment (95% vs 68%, p = 0.056). Before 1 year of treatment, 4 children developed viral resistance to ddI, and all of them had an AUC <0.85 mg/L.h. A C_max >0.4 mg/L was also correlated to a better viral load decrease and to the absence of viral resistance to ddI.

Conclusions:  A 360-mg/m² ddI dose administered as tablets should be a more appropriate dose to improve efficacy than 240 mg/m² in these children. However, data on adverse events with this dosage are missing.