Effect of food and pharmacokinetic variability on didanosine systemic exposure in HIV-infected children

The effect of food on didanosine bioavailability and interpatient pharmacok inetic variability was examined in children infected with human immunodefic iency virus type 1 (HIV-1). Didanosine pharmacokinetics were determined dur ing fasting and fed conditions in HIV-infected children enrolled in the Ped iatric AIDS Clinical Trials Group Protocol 144 randomized to receive didano sine at 50 mg/m(2) or 150 mg/m(2) orally every 12 hr, Pharmacokinetic param eters from patients in the low (n = 39) and high (n = 38) dosing groups wer e not significantly different, but intersubject variability was substantial . The fraction absorbed was higher while fasting than with food (0.27 +/- 0 .13 versus 0.19 +/- 0.09, p < 0.0001); the zero order absorption rate was f aster (0.48 +/- 0.31 versus 0.76 +/- 0.72 hr, p = 0.003); and the plasma ha lf-life was shorter (0.93 +/- 0.43 versus 1.39 +/- 0.65 hr, p < 0.0001). Th e lower fraction absorbed with food was offset by the absorption rate becom ing rate limiting for elimination, resulting in similar areas under the con centration-time curves (normalized to 100 mg/m(2)) when fasted (853.9 +/- 4 65.8 mu g/liter hr) versus fed (796.3 +/- 367.5 mu g/liter hr). Oral cleara nces during fasting (152.5 +/- 81.7 liters/hr/m(2)) and fed states (163.6 /- 99.3 liters/hr/m(2)) were similar, but these values in children are subs tantially higher than previously reported for adults. The systemic exposure (i.e., AUG) of didanosine was highly variable in children but similar in t he presence and absence of food. Administration of didanosine with food in children may be permissible if total systemic exposure rather than maximum plasma concentration is sufficient for antiretroviral activity. The higher oral clearance and substantial pharmacokinetic variability suggest the need to reexamine current didanosine dose recommendations for HIV-infected chil dren.