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

Abstract

We studied the pharmacokinetics of intravenously and orally administered lamivudine 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 simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 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 dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=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 serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.

FIG. 1

Two-compartment pharmacokinetic model with differential equations describing concentration or amount of lamivudine in each compartment. C_c is the concentration of lamivudine in the central compartment at time t, X_p is the amount of drug in the peripheral compartment at time t, X_a is the amount of drug at the absorption site at time t, k₀ is the rate of drug infusion for the intravenous dose, k_a is the absorption rate constant for the oral dose, V_c is the volume of the central compartment, k_cel is the elimination rate constant, and k_cp and k_pc are the rate constants for transfer of drug from the central to peripheral compartment and from the peripheral to central compartment, respectively.

FIG. 2

Serum lamivudine concentrations after intravenous (○) and oral (□) doses of 10 mg/kg in a single patient. Points represent the measured serum concentrations, and lines represent the model-predicted concentrations for intravenous (—) and oral (- - - ) administration from simultaneous fitting of the intravenous and oral drug concentration-time data.

FIG. 3

Correlation between dose of lamivudine and AUC for intravenous (A) and oral (B) administration over a dosage range from 0.5 to 10 mg/kg. Points and bars represent the mean and SD at each dose level. The line was constructed by normalizing the AUCs at all dose levels to a dose of 10 mg/kg, taking the mean of the normalized AUCs, and drawing a line from the origin through the mean, normalized AUC.

FIG. 4

Correlation between age and lamivudine clearance normalized to body weight (A) and body surface area (B). The equations for the regression lines shown in panels A and B are CL (liter/kg/h) = 0.68 − 0.018 · age (r = 0.425; P = 0.0022) and CL (ml/min/m²) = 242 − 1.7 · age (r = 0.096; P = 0.50), respectively.

FIG. 5

Limited-sampling strategy for oral lamivudine. The model was developed by stepwise regression analysis of data for patients treated at the 10-mg/kg dose level (A) and validated with data for patients treated at the 2-mg/kg dose level (B). The equation for estimating the AUC from the serum concentrations at 2 (C_2h) and 6 (C_6h) h after the dose is AUC = 2.51 · C_2h + 6.46 · C_6h + 0.97 · dose. The graphs plot the AUC predicted from the limited-sampling model versus the actual AUC derived from the entire set of measured serum drug concentrations by the trapezoidal method. The line is the line of unity.