Safety and single-dose pharmacokinetics of abacavir (1592U89) in human immunodeficiency virus type 1-infected children

Abacavir (formerly 1592U89) is a potent 2'-deoxyguanosine analog reverse tr anscriptase inhibitor that has been demonstrated to have a favorable safety profile in initial clinical trials with adults with human immunodeficiency virus (HIV) type 1 infection. A phase 1 study was conducted to evaluate th e pharmacokinetics and safety of abacavir following the administration of t wo single oral doses (4 and 8 mg/kg of body weight) to 22 HIV-infected chil dren ages 3 months to 13 years. Plasma was collected for analysis at predos e and at 0.5, 1, 1.5, 2, 2.5, 3, 5, and 8 h after the administration of eac h dose. Plasma abacavir concentrations were determined by high-performance liquid chromatography, and data were analyzed by noncompartmental methods. Abacavir was well tolerated by all subjects. The single abacavir-related ad verse event was rash, which occurred in 2 of 22 subjects. After administrat ion of the oral solution, abacavir was rapidly absorbed, with the time to t he peak concentration in plasma occurring within 1.5 h postdosing, Pharmaco kinetic parameter estimates were comparable among the different age groups for each dose level. The mean maximum concentration in plasma (C-max) and t he mean area under the curve from time zero to infinity (AUC(0-infinity)) i ncreased by 16 and 45% more than predicted, respectively, as the abacavir d ose was doubled. from 4 to 8 mg/kg (C-max increased from 1.69 to 3.94 mu g/ ml, and AUC(0-delta) increased from 2.82 to 8.09 mu g . h/ml). Abacavir was rapidly eliminated, with a mean elimination half-life of 0.98 to 1.13 h. T he mean apparent clearance from plasma decreased from 27.35 to 18.88 ml/min /kg as the dose increased. Neither body surface area nor creatinine clearan ce were correlated with pharmacokinetic estimates at either dose. The exten t of exposure to abacavir appears to be slightly lower in children than in adults, with the comparable unit doses being based on body weight, In concl usion, this study showed that abacavir is safe and well tolerated in childr en when it is administered as a single oral dose of 4 or 8 mg/kg.