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 μM 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.

Evaluation of effect of impaired renal function on lamivudine pharmacokinetics

“…Lamivudine concentrations were satisfactorily described by a two‐compartment model. Lamivudine freely penetrates tissue beyond the systemic circulation and is able to distribute through a peripheral compartment . The apparent elimination clearance and AUC 0–24h were consistent with previous studies .…”

Age-dependent Pharmacokinetics of Lamivudine in HIV-infected Children

“…Our study demonstrates that the recommended pediatric lamivudine dose of 4 mg/kg does not lead to similar plasma AUC and C max of lamivudine in children younger than 6 years of age when compared with older children or adults. It must be noted that the increased apparent clearance (corrected for body weight) of lamivudine in younger children has been previously reported 2 , 16 , 17 . Nevertheless, the dosing recommendations for lamivudine in children aged 3 months to 16 years remain unchanged, are similar for the oral solution and the tablets despite a potential difference in bioavailability between these two formulations in children, and all age groups continue to receive the same dose of lamivudine per kilogram body weight.…”

Dose evaluation of lamivudine in human immunodeficiency virus‐infected children aged 5 months to 18 years based on a population pharmacokinetic analysis

“…Also, the full paediatric age range is covered, with a large proportion of children below the age of 3 years [ n = 16 (18.8%) in the dataset used for model‐building; n = 41 (22.8%) in total]. The two‐compartment model used to describe the data is in agreement with previously developed models . In order to obtain reliable estimates of the peripheral volume, the model had to be simplified by stating that the central and peripheral volume of distribution were equal to each other (Table ); however, this did not lead to reduced descriptive or predictive values (Figures and S1).…”