In this study, a model of LPV disposition in children and adolescents 4 through 18 years of age was developed and validated by a visual predictive check of the distribution of LPV concentrations in 1,000 model-simulated patients compared with the distribution of LPV concentrations in the study population. In the final model, LPV was rapidly absorbed after an initial formulation-dependent delay, with an apparent V
that increased nonlinearly as a function of weight over age. Overall, the drug CL varied according to weight0.75
, in accordance with the allometric scaling principles in children suggested by Anderson et al. (2
), among others.
Because of high correlation between V and CL, the model was parameterized in terms of fractional elimination (kel) that declined with increasing weight. The CL-V correlation indicates that in the model clearance of LPV was driven primarily by the apparent V, which raises the possibility that LPV bioavailability may have been variable. Due to the lack of an intravenous formulation, the absolute bioavailability of LPV has not been established. Close inspection of Fig. reinforces the fact that most of the LPV PK variability is in absorption and bioavailability, since after an individual trajectory peaks, it generally declines consistently thereafter. In other words, between-individual variability is larger than within-individual variability, which enables the close fit shown in Fig. versus that in Fig. .
In adults given the standard dose of 400/100 mg LPV/RTV twice daily, the Kaletra package insert reports a steady-state LPV AUC of 92.6 mg·h/liter, a Cmax of 9.8 mg/liter occurring 4 h after a dose, and a Ctrough of 7.1 mg/liter. For children given 230/57.5 mg/m2 LPV/RTV twice daily, the package insert reports a steady-state LPV AUC of 72.6 mg·h/liter, a Cmax of 8.2 mg/liter occurring 4 h after a dose, and a Ctrough of 3.4 mg/liter. The children in our study received a median LPV dose of 275 mg/m2, which is 20% higher than the recommended dose. The median LPV AUC, Cmax, and Ctrough were correspondingly higher than those reported for children in the package insert and were similar to adult values, with the exception of the Ctrough, which was slightly lower than that of adults.
With large interpatient variability in LPV PK, it is very important to estimate the chance of a child on ART having suboptimal LPV exposure. Other studies have suggested that the currently recommended dose of LPV/RTV might result in suboptimal exposure in HIV-infected children (4
). Based on our PK model and the LPV pharmacodynamic models by Hsu et al. and Podzamczer et al. (13
), we have shown that the majority of children are unlikely to achieve therapeutic plasma LPV concentrations against virus that is moderately resistant to LPV, at degrees far below the clinical cutoffs suggested by current phenotypic resistance testing. Furthermore, patients with fewer than two active background antiretroviral agents would have even higher IQ targets (13
) and would require correspondingly higher doses of LPV. It is this population of PI-experienced patients who would most likely derive direct benefit from measurement of plasma LPV concentrations and dose adjustment if necessary to avoid excessive dependence on the remaining drugs in the therapeutic regimen. Separate analysis in this cohort of HIV-infected children will compare the measured relationships of individual LPV PK and phenotypic and genotypic IQs to virologic responses.
In this study, a model of LPV disposition in pediatric patients >4 years of age was developed and validated by a visual predictive check of the distribution of LPV concentrations in 1,000 model-simulated patients compared with the distribution of LPV concentrations in the study population. Based on this PK population model, the currently recommended dose of LPV/RTV appears to be adequate for children infected with wild-type virus but is unlikely to provide adequate inhibitory concentrations for even moderately resistant HIV. PI-experienced HIV-infected children would likely benefit from longitudinal, repeated LPV drug measurement in plasma in combination with resistance evaluation to ensure that LPV dosing is sufficient to maximize the contribution of LPV to virologic control.