The primary objectives of this study were to determine a dosing regimen for efavirenz, given in combination with nelfinavir and at least one NRTI, in children and to evaluate the safety and virologic responses of this combination antiretroviral regimen. Before the initiation of this study, efavirenz had not been administered to children. Thus, this study had phase I objectives of establishing the pharmacokinetic profile and pediatric dose of efavirenz and phase II objectives of evaluating safety and efficacy. To meet these objectives, this study employed an AUC-controlled strategy for both efavirenz and nelfinavir. The target AUC range for efavirenz was selected to find a dose of efavirenz that achieved concentrations at least equivalent to those of the “ average” adult receiving a dose shown to be safe and associated with a significant virologic response. For nelfinavir, the target AUC choice differed from that of efavirenz because nelfinavir was already approved by the US Food and Drug Administration (FDA) for treatment of children and adults; and thus, theoretically, there was no need to find the right dose for children, but rather the objective was to set a “safety net” to identify children who had unacceptably low concentrations and may be at an increased risk for a suboptimal virologic response. At week 10, 74 and 82% of children in this study had AUC values in the target range for efavirenz and nelfinavir, respectively. These data, in conjunction with previously published virologic response data, indicating that 81% of children on treatment achieved a viral load of less than 400 copies/ml at week 48 (70% had less than 50 copies/ml) and that the regimen was safe and well tolerated, provide support to conclude that this study met the intended objectives.1,2
The pharmacokinetic characteristics found for efavirenz and nelfinavir in these children indicated two important differences compared with adults. First, the mean week-2 CL/F
for efavirenz of 0.21 l/h/kg is approximately 1.5-fold faster than in adults, and for nelfinavir, the mean week-2 CL/F
of 2.32 l/h/kg is approximately 3.4-fold faster. These data reinforce that children are pharmacokinetically distinct from adults. For efavirenz and nelfinavir, simply scaling adult doses to children on a body weight basis would have substantially underdosed these children, and highlights the need for pediatric-specific dosing recommendations. The pharmacokinetic characteristics of nelfinavir in these children compared well with those reported in other smaller studies.3
Second, in the group of 34 children who had pharmacokinetic evaluations performed at both weeks 2 and 56, there were significant changes in their pharmacokinetic characteristics for both efavirenz and nelfinavir over this 1-year period. The CL/F
of efavirenz increased by 37%, whereas that for nelfinavir increased by 62%. The physiologic change in these children that resulted in an increase in CL/F
for efavirenz and nelfinavir between weeks 2 and 56 cannot be identified with certainty. However, the pharmacokinetic evidence points to a change in metabolic capacity rather than bioavailability. For example, the 34 children who had pharmacokinetic evaluations at both weeks 2 and 56 had a mean efavirenz elimination half-life at week 2 of 40.9 h and at week 56 of 29.3 h. Had the increase in CL/F
been due to a change in bioavailability and not metabolic capacity, the half-life would have remained unchanged. These data indicate a need for an improved understanding of the ontogeny of the drug-metabolizing pathways involved in efavirenz and nelfinavir clearance. A contribution of other factors to the change in drug clearance over time, such as HIV infection itself and associated opportunistic infections, cannot be excluded. These data indicate that age- or weight-based (doses in this study were adjusted if weight changed by 25%) dosing strategies may not reliably capture developmental changes in drug disposition and that ongoing monitoring of plasma concentrations for drugs such as antiretroviral agents where there are profound consequences of therapeutic failure, is necessary.
Those children who reached undetectable HIV RNA at week 8 had higher efavirenz and nelfinavir AUCs and trough concentrations at week 2 than those who had HIV RNA levels > 400 copies/ml. These exposure–response relationships were supported by analyses showing that significantly more children who had AUC values for efavirenz and nelfinavir greater than the first quartile had HIV RNA ≤ 400 copies/ml, and additionally by logistic regression analyses showing that the week-2 AUC values had independent contributions to predicting an undetectable HIV RNA at week 8. These findings are consistent with other literature demonstrating exposure–response relationships and treatment guidelines for minimum trough concentrations of efavirenz and nelfinavir for antiretroviral naive adults.4
For example, efavirenz trough concentrations < 1 mg/l were associated with a 50% rate of virologic failure versus a 22% rate when concentrations were between 1 and 4 mg/l in a population of 130 adult patients receiving antiretroviral therapy for more than 3 months.5
Morning trough concentrations of nelfinavir less than 1.4mg/l (also expressed as a concentration ratio of less than 0.9) were found to increase significantly the risk of virologic failure.6
A prospective study of nelfinavir therapeutic drug monitoring in 92 adult patients demonstrated an improved virologic response after 1 year of follow-up with 81% of subjects who received therapeutic drug monitoring having HIV RNA < 500 copies/ml compared with 59% of those who received standard dose therapy.7
The number (and percent) of children who achieved the desired targets for efavirenz and nelfinavir at the week-56 pharmacokinetic evaluation were 16 (47%) and 25 (74%), respectively. There was no difference in the proportion of children who achieved the target and had or did not have HIV RNA < 400 copies/ml, although these comparisons were limited by the small sample size, and any child with an HIV RNA > 10,000 copies/ml at week 48 was excluded from further participation. The change in CD4 cell count from baseline to week 48 was weakly associated with efavirenz Cmax
and nelfinavir CL/F
at week 56. The proportion of children who achieved the target AUC values at week 56 was less than that at week 10, and can be attributed to significant, and unexpected, increases in efavirenz and nelfinavir oral clearance. There was also no difference in pharmacokinetic characteristics at week 56 between those children with HIV RNA above and below 400 copies/ml. These data suggest that the cause of viremia in these children likely cannot be attributed to differences in pharmacokinetics. One logical consideration is poor adherence. We have previously shown in children in this study that those who had high variability in their monthly random efavirenz concentrations over time, as a putative metric of low adherence, were significantly more likely to experience virologic rebound.8
The antiretroviral regimen and innovative dosing strategies used in this study demonstrated a high rate of virologic success in these HIV-infected children. A comparison of pediatric antiretroviral therapy studies found that those in which doses were adjusted based on measured concentrations of antiretroviral drugs resulted in superior virologic responses compared with those that used fixed-dose regimens. 9
This study accomplished its objectives without prior pharmacokinetic knowledge of efavirenz in children, by using an AUC-controlled paradigm and targeting adult levels of systemic exposure (but not adult doses). This approach was also extended to nelfinavir; although there was an FDA-approved dose for children, there was quite limited pediatric experience. Collectively, the pediatric HIV therapeutic experience advances an argument for therapeutic drug monitoring of antiretroviral agents in this population. In fact, such a recommendation is included in the British HIV Association treatment guidelines and discussed in those of the USA Working Group on Medical Management of HIV-Infected Children.10,11
Knowledge of genetic differences in drug-metabolizing enzymes will improve our understanding of interpatient variability in pharmacokinetics and pharmacodynamics. For example, recent data for efavirenz in children indicate that the CYP2B6
-G516T polymorphism accounts for a 2.3-fold difference in clearance on a l/h/m2
The integration of pharmacogenomics with therapeutic drug monitoring might improve the application and usefulness of this strategy.
The challenges of antiretroviral therapy, indeed all pharmacologic interventions in children, are not trivial and require, for example, the availability of suitable pediatric formulations, knowledge of age-specific pharmacokinetic characteristics, and the ability to account for the effects of developmental changes in drug pharmacokinetics over time. We believe that the strategy described here can be extended to other antiretroviral agents and other drugs to increase the effectiveness and efficiency of pediatric drug development.