Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children

We studied the pharmacokinetics of intravenously and orally administered la mivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simulta neously fitted to the serum drug concentration-time data obtained after int ravenous and oral administration. The maximal concentration at the end of t he 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with th e dose. The mean clearance of lamivudine (+/- standard deviation) in the ch ildren,vas 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m(2) of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age depen dent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administratio n, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentr ations were maintained above 1 mu M for greater than or equal to 8 h of 24 h on the twice daily oral dosing schedule with doses of greater than or equ al to 2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured se rum drug concentration. A limited-sampling strategy was developed to estima te the area under the concentration-time curve for concentrations in serum at 2 and 6 h.