This is the first study to evaluate the safety and pharmacokinetics of abacavir in HIV-infected children. The results indicate that abacavir is rapidly absorbed following the administration of single oral doses of 4 and 8 mg/kg. The pharmacokinetics of abacavir are not strictly dose proportional in the population studied, as indicated by the greater than predicted increases in Cmax (16%) and AUC0–∞ (45%) observed when the administered dose was doubled from 4 to 8 mg/kg. Our study did not identify a strongly predictable relationship between measures of growth and development and the pharmacokinetic estimates of abacavir by stepwise regression analysis.
Abacavir was well tolerated by HIV-infected children. A rash attributed to abacavir occurred in 2 of 22 children who received the 8-mg/kg dose. The favorable safety profile of abacavir is well supported by preclinical toxicology studies with animals (7
) and by an initial dose-escalation study with adults (16
One child (subject 17) clearly presented values for all pharmacokinetic parameters that were very different from those for the other children in the study population. At the time of screening, this 6-month-old patient received a waiver of the exception criteria because she weighed less than 5 kg. Because abacavir is eliminated primarily by metabolism rather than by renal filtration, one possible reason for this subject’s results may be unusually underdeveloped metabolic pathways resulting in elevated AUC0–∞ and Cmax values or prolonged t1/2β values.
A comparison of the pharmacokinetic results obtained in the present study with those reported previously for adults (16
) on a milligram-per-kilogram dose basis yield a number of observations. By using a mean body weight of 70 kg, comparable doses of abacavir in HIV-infected adults who received the 300- and 600-mg doses were approximately 4 and 8 mg/kg, respectively. At these doses, the least-squares mean values of AUC0–∞
were approximately 45 to 48% lower in children than in adults (2.57 or 7.46 versus 4.93 or 13.5 μg · h/ml), indicating lower bioavailability in children. The least-squares mean values of Cmax
were approximately 15 to 34% lower in children than in adults (1.58 or 3.68 versus 2.39 or 4.36 μg/ml). The median Tmax
occurred over the range of 0.5 to 1.5 h following the administration of abacavir as an oral solution formulation. These times are very similar to the Tmax
range noted for adults (1.0 to 1.7 h) following the administration of abacavir as a tablet formulation, suggesting that absorption rates may be comparable between children and adults. The least-squares mean value of t1/2β
was approximately 21 to 33% shorter for children than for adults (0.93 or 1.11 versus 1.17 or 1.66 h), which represents an actual difference of 44 min between the lowest and highest values. The lower AUC0–∞
and the shorter t1/2β
were consistent with the more rapid apparent clearance from children than from adults (25.62 or 17.84 versus 12.55 or 10.14 ml/min/kg). These results suggest that children may need a higher dose of abacavir than adults on a milligram-per-kilogram basis in order to achieve the same exposure.
The differences in pharmacokinetics of abacavir between children and adults are consistent with the results reported in previous studies in which the pharmacokinetics of other reverse transcriptase inhibitors were evaluated in children with HIV infection. Balis et al. (3
) reported that with the exception of oral bioavailability the pharmacokinetics of didanosine in children appeared to be comparable to those in adults. Oral bioavailability, however, was significantly lower in children (35 versus 19%) (3
). Chadwick et al. (6
) reported that the concentrations of zalcitabine in plasma were lower and that the t1/2
was shorter in children than in adults given comparable doses. Kline et al. (15
) indicated that higher doses (on a milligram-per-kilogram basis) of stavudine than those administered to adults (0.5 or 1 mg/kg/day) were needed to achieve equivalent drug exposure in children (1 or 2 mg/kg/day) (15
). Similarly, Lewis et al. (17
) reported that consistently lower concentrations of lamivudine in serum were recorded in children compared with those that were recorded in adults, suggesting the need for the administration of higher doses to children to achieve doses equivalent to those achieved in adults. In addition, the t1/2
in serum tended to be shorter in children than in adults (1.7 versus 2.5 h). Studies have shown that the pharmacokinetics of zidovudine in children older than several months of age are similar to those in adults (1
). However, different pharmacokinetics have been reported in infants under 2 weeks of age, including a longer t1/2
in serum, greater bioavailability, and a lower rate of clearance (4
The median plasma abacavir concentration exceeded the IC50
noted in studies of clinical isolates from zidovudine-naive patients with <300 CD4+
for at least 2.5 and 4.5 h for the 4- and 8-mg/kg doses, respectively. These times are consistent with those obtained from a dose-ranging study of abacavir with adults (3.5 and 4.5 h for the 300- and 600-mg doses, respectively) (16
Because of the small number of patients enrolled in this study, no strongly predictive associations between demographic and pharmacokinetic parameters were noted. A large study that uses the population approach to data analysis is warranted to further evaluate the demographic parameters that are predictors of abacavir pharmacokinetics.
In summary, the results of this study confirm the desirable pharmacokinetic properties and the favorable safety profile of abacavir for use in the treatment of HIV-infected children. Studies are under way to evaluate the clinical efficacy of the 8-mg/kg dose of abacavir for the treatment of HIV-1 infection in pediatric patients. Use of this dose is supported by the pharmacokinetic observations in the present study.