title: Developmental pharmacokinetic changes of Lamivudine in infants and children.
abstract: Lamivudine is a nucleoside reverse transcriptase inhibitor widely used in infants and children in combination antiretroviral therapy to treat human immunodeficiency virus (HIV) infection. Developmental changes in lamivudine pharmacokinetic disposition were assessed by combining data from 7 studies of lamivudine (Pediatric AIDS Clinical Trials Group 300, 353, 356, 358, 386, 1056, and 1069) representing subjects across the pediatric age continuum. A population pharmacokinetic model was developed to identify factors that influence lamivudine disposition. Age and Thai race were independent predictors of apparent clearance (CL/F), whereas the use of a fixed drug combination formulation (GPO-VIR) was an independent predictor of bioavailability, with CL/F more than doubling from birth to adolescence. Serum creatinine was not associated with CL/F. Monte Carlo simulations were used to compare the lamivudine exposure achieved with World Health Organization (WHO) weight band and Food and Drug Administration (FDA) label dosing recommendations. WHO dosing yielded higher exposure during the first few months of life, but this difference was less pronounced between 6 months and 14 years of age. Overall, both FDA and WHO dosing provided similar AUC values to those previously reported in HIV-infected adults. Lamivudine WHO weight band dosing results in therapeutic exposure in infants and children and may improve drug dosing in resource-limited countries.
authors.affiliation: UC San Diego Pediatric Research Center, 7910 Frost St, #360, San Diego, CA 92123, USA. atremoulet@ucsd.edu
authors.forename: Adriana H
authors.initials: AH
authors.lastname: Tremoulet
authors.forename: Mina
authors.initials: M
authors.lastname: Nikanjam
authors.forename: Tim R
authors.initials: TR
authors.lastname: Cressey
authors.forename: Kulkanya
authors.initials: K
authors.lastname: Chokephaibulkit
authors.forename: Ross
authors.initials: R
authors.lastname: McKinney
authors.forename: Mark
authors.initials: M
authors.lastname: Mirochnick
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000375:Aging / Q000097:blood; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003404:Creatinine / Q000097:blood; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000517:prevention & control; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D019259:Lamivudine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008954:Models, Biological; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D003404:Creatinine