ABC is a useful and effective antiretroviral agent when used as part of combination therapy for the treatment of children with HIV The Paediatric European Network of Treatment of AIDS (PENTA) 5 trial2
compared the activity of 3 randomly assigned dual-NRTI regimens (AZT/3TC, AZT/ABC, and 3TC/ABC) in previously untreated children. The dose of ABC was 8 mg/kg given twice daily, which is consistent with current dosing recommendations. Results demonstrated that ABC-containing dual-NRTI regimens produced larger reductions in viral load than standard AZT/3TC regimens. In particular, the ABC/3TC regimen resulted in a greater and more sustained (up to 48 weeks) viral load reduction of the combinations studied.
The PK parameters of the present study are comparable to previously published data in children receiving 8 mg/kg of ABC.6,13
Hughes et al and Jullien et al reported mean CL/F
values of 18.9 and 15.8 mL/min per kg and mean AUC values of 8.1 and 8.5 μg·hr/mL, respectively, in populations that were limited primarily to prepubescent subjects. The current study revealed mean CL/F
and AUC values of 20.3 mL/min per kg and 8.4 μg·hr/mL overall with no appreciable differences between the 2 study groups. As shown in , despite the large variability in oral clearance and AUC, subjects in Tanner stages 3–5 had similar values (within 20%) to the younger cohort of Tanner stages 1–2. Other PK parameters were also not discernibly different, and in the regression analysis, there were no associations found between PK parameters (weight adjusted) and age or Tanner stage.
Comparing the results of the present study with those previously reported in adults4,8
generated some interesting observations. Kumar et al and Weller et al studied ABC PKs in adults (average age 38 and 39 years, respectively) receiving 600 mg (approximately 8 mg/kg) and reported mean CL/F
values of 10.2 and 11.5 mL/min per kg, respectively. The recommended adult dose of 300 mg twice daily has been shown to produce AUCs in the range of 5–6 μg·hr/mL,1,4,8,14–16
whereas single-dose studies in adults given 600 mg have generated AUCs in the range of 11–16 μg·hr/mL.4,8,14
Our present study yielded a mean AUC of 8.4 μg·hr/mL, which falls in between the 4 and 8 mg/kg doses studied in adults. It is apparent that oral clearance and systemic exposure of ABC in adolescents are more comparable to values in children than in adults at the same milligram per kilogram dose (ie, 8 mg/kg; ).
Comparison of Mean PK Parameters of Single-Dose ABC
In all the postpubescent adolescents in this study, the 8 mg/kg dose exceeded 300 mg, yet the overall ABC exposure was similar to younger children. Assuming dose linearity, if the dose had been limited to a maximum of 300 mg, the AUC in the adolescent group (Tanner ≥ 3) would have been reduced by about a third and the resulting AUC of 5.7 ± 2.2 would have been lower than the younger group (Tanner 1–2) but similar to adults. Therefore, as older adolescents continue to develop and gain weight, a 300-mg dose will steadily provide less drug on a milligram per kilogram basis. If clearance normalized to body size remains constant during this time of growth, then further reductions in AUC would be expected; thus, potentially increasing the likelihood of virologic failure.
This study demonstrated that ABC clearance is highly correlated with the extent of metabolite formation. After oral administration, ABC undergoes rapid and extensive absorption and is eliminated primarily by metabolism to the GLU and CAR metabolites with less than 5% eliminated unchanged in the urine. The enzymes UDP-glucuronosyltransferases, alcohol dehydrogenase, and aldehyde dehydrogenase-2 account for approximately 70% of ABC metabolism.14
These primary enzymatic pathways have known genetic polymorphisms17–19
shown to substantially alter clearance of known substrates. Moreover, there are differences in ethnic prevalence for genotype and phenotype for UDP-glucuronosyltransferases,20,21
alcohol dehydrogenase, and aldehyde dehydrogenase-2.22
We found that the ratios of metabolites to parent compound, expressed as either AUC or 6-hour concentrations, show a relationship with ABC CL/F
. Although measuring systemic exposure (AUC) of all 3 compounds is not practical in a clinical setting, the possibility exists that a single blood sample at the 6-hour time point could be useful in predicting subjects with high ABC clearance, more so with the GLU:ABC ratio.
There are some limitations of this study worth mentioning. First, this study used the ABC oral solution to provide a flexible means to dose subjects over a wide range of body size. Administering the solution aided in giving a more accurate milligram per kilogram dose than could be done using the commercially available tablet, which only exists in a 300 mg strength. Although the solid oral dosage form is more commonly used in adolescents, the bioavailability of the solution has been shown to be equivalent to the tablet.5
It is also worth noting that intracellular concentrations of carbovir triphosphate, the active moiety, were not measured in this study. Currently, it is impractical and time consuming to measure carbovir triphosphate in a clinical setting.
Rapid ABC absorption, resulting in 10 subjects with the first concentration being the Cmax, limited the ability to characterize the absorption phase with a high level of precision. This means that the true peak concentrations may have been missed and thus AUC would be underestimated by the noncompartmental method. However, comparing AUC estimates by 2 separate methods yielded similar results (data not shown). A related concern is that AUC was determined over an 8-hour sampling period for a medication commonly given twice daily. However, it is estimated that <3% of the total AUC can be accounted for in the period after 8 hours (for all subjects: mean 8-hour concentration = 0.124 μg/mL and mean kel = 0.57/h).
This study was not powered to detect modest age-related PK differences. Thus, although we saw no differences between the 2 subject groups, we cannot rule out the possibility that a moderate difference exists. Although there was a frequent use of protease inhibitors and other nonnucleoside reverse transcriptase inhibitors, there is no indication that these concomitant drugs affect ABC disposition in this population.
In conclusion, the results of this study describe the PKs of 8 mg/kg ABC in an HIV-infected adolescent population. We found that both GLU and CAR metabolites:ABC ratios are able to discriminate subjects with high and low ABC clearance. This finding needs further confirmation but could potentially have clinical relevance for ABC and other similarly metabolized drugs. PK data from the present study compared with previously published data of ABC reveal that CL/F in adolescents is comparable to that in children, and lower AUCs would be expected in older adolescents if given the adult-referenced maximum dose of 300 mg twice daily. As a result, further study of efficacy, safety, and tolerability is warranted in an older adolescent population and young adult population with doses of 8 mg/kg (maximum 600 mg) twice daily.