Is the recommended once-daily dose of lamivudine optimal in West African HIV-infected children?
We aimed in this study to describe lamivudine concentration-time courses in treatment-naïve children after once-daily administration, to study the effects of body weight and age on lamivudine pharmacokinetics, and to simulate an optimized administration scheme. For this purpose, lamivudine concentrations were measured in 49 children after at least 2 weeks of didanosine-lamivudine-efavirenz treatment. A total of 148 plasma lamivudine concentrations were measured, and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Children were divided into two groups, according to their pharmacokinetic parameters, thanks to tree regression analysis. For each patient, the area under the curve was derived from estimated individual pharmacokinetic parameters. Different once-daily doses were simulated in each group, to obtain the same exposure in children as the mean effective exposure in adults (8.9 mg/liter.h). A two-compartment model in which the slope of distribution is assumed to be equal to the absorption rate constant adequately described the data. Parameter estimates were standardized for a mean standard body weight using an allometric model. Children were then divided into 2 groups according to body weight: CL/F was significantly higher in children weighing less than 17 kg (1.12 liters/h/kg) than in children over 17 kg (0.95 liters/h/kg; P=0.01). The target mean AUC of 8.9 mg/liters.h was obtained with a 10-mg/kg once-daily lamivudine (3TC) dose for children below 17 kg; the recommended dose of 8 mg/kg seems to be sufficient in children weighing more than 17 kg. These assumptions should be prospectively confirmed.
EA 3620, Université Paris-Descartes, Unité de Recherche Clinique, Hôpital Tarnier, 89 Rue d'Assas, 75006 Paris, France. naim.bouazza@cch.aphp.fr
Naïm
N
Bouazza
Déborah
D
Hirt
Christophe
C
Bardin
Serge
S
Diagbouga
Boubacar
B
Nacro
Hervé
H
Hien
Emmanuelle
E
Zoure
François
F
Rouet
Adama
A
Ouiminga
Stephane
S
Blanche
Philippe
P
Van De Perre
Jean-Marc
JM
Tréluyer
Philippe
P
Msellati
Saik
S
Urien
D000293:Adolescent; D000354:Africa, Western; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019540:Area Under Curve; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D008297:Male; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; C098320:efavirenz; D016049:Didanosine