This article describes lamivudine pharmacokinetics in 580 children from 2 days to 18 years of age. 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 (12
). The apparent elimination clearance and AUC0–24
in each age group were consistent with those in previous studies (). The apparent elimination clearance (CL/F
= 31 liters/h/70 kg) was consistent with previous adult studies: 29.6 liters/h (18
) and 26.7 liters/h (10
). The apparent volume of distribution (central plus peripheral) was consistent with previous adult studies: 205.4 liters/70 kg versus 128 liters (17
) and 238 liters (5
The population model was also used to investigate the effect of growth (body weight) and maturation (age) on pharmacokinetic parameters. In our model, after allometric scaling of the parameters, an effect of age, PMA, on clearance was also observed. The PMA parameters for the clearance, γ and PMA50
, are similar to those reported for vancomycin (3
). The PMA50
found in this study for lamivudine (59 weeks) is greater than the PMA50
of 48 weeks reported for maturation of the glomerular filtration rate (GFR) (21
). The clearance of 31 liters/h/70 kg for a drug that is 70% eliminated by the kidney and not highly protein bound means that it must be excreted by tubular secretion. The later maturation of lamivudine clearance may suggest that tubular secretion develops later than the GFR. On the other hand, the discrepancy between the rate of maturation of GFR and maturation of lamivudine CL/F
should be addressed also as follows: older infants may have a lower CL/F
than the value that could be expected from PMA and weight alone because they would be sicker, having been infected longer with HIV.
According to this model, clearance increases gradually up through the first years of age. This relationship between lamivudine clearance and age was supported by the study by Tremoulet et al. (23
), which demonstrated the rapid maturation of renal function occurring from birth and persisting during the subsequent few weeks of life.
The variation in lamivudine clearance could be explained by the progressive maturation of renal function with age and body weight during the first years of life.
No relationship between concentration and efficacy of lamivudine in children has been successfully demonstrated. Thus, we considered the range of AUC0–24
values observed in adults from previous studies following administration of 300 mg OAD of lamivudine (7
). Considering this range of AUC0–24
values, the calculated dose needed to reach this adult exposure according to age shows that the transition from 4 mg/kg/day to 8 mg/kg/day at 6 weeks of age (FDA recommendation) should be reconsidered. Our simulations show that a dosing scheme gradually increasing the dose (mg/kg) according to weeks of age seems to maintain exposure closer to that in the adult and better reflects the maturation of renal function occurring from birth and persisting during the first weeks of life.
The actual FDA recommendations for lamivudine in older children (150 mg/day from 14 to 21 kg of body weight, 225 mg/day from 21 to 30 kg, and 300 mg/day thereafter) are close to our recommendations. In conclusion, this study reports lamivudine pharmacokinetics in children ranging from neonates to adolescents. The pharmacokinetic parameters were consistent with those from previous studies. The lamivudine elimination clearance is related to the maturation of renal function and varies as a function of age and body weight. Moreover, this modeling reflects fully mature adult values. According to simulations, to be closer to adult exposure, children should receive the following lamivudine doses: 4 mg/kg/day from birth to 8 weeks of age, 5 mg/kg/day from 8 to 16 weeks of age, 6 mg/kg from 16 to 25 weeks of age, 8 mg/kg/day from 25 weeks of age to 14 kg of body weight, 150 mg/day from 14 to 25 kg of body weight, 225 mg/day from 25 to 35 kg of body weight, and 300 mg/day thereafter.