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 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.
Mueller
B U
BU
Pediatric Branch and Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland, USA. mueller_b@a1.tch.harvard.edu
Lewis
L L
LL
Yuen
G J
GJ
Farley
M
M
Keller
A
A
Church
J A
JA
Goldsmith
J C
JC
Venzon
D J
DJ
Rubin
M
M
Pizzo
P A
PA
Balis
F M
FM
D000284:Administration, Oral; D000293:Adolescent; D019380:Anti-HIV Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000134:cerebrospinal fluid*; D006801:Humans; D007223:Infant; D007275:Injections, Intravenous; D019259:Lamivudine / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D008297:Male
D019380:Anti-HIV Agents; D019259:Lamivudine