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Recommended Dose of Lopinavir/Ritonavir is Sub-optimal in Protease Inhibitor-experienced Children
Natella Rakhmanina*1,2, J Van Den Anker1,2, M Van Guilder3, S Soldin1,2, K Williams1, A Baghdassarian1,2, and M Neely3
1Children`s Natl Med Ctr, Washington, DC, US; 2George Washington Univ, Washington, DC, US; and 3Univ of Southern California, Los Angeles, US
Background: Lopinavir/ritonavir (LPV/rtv, Kaletra),
the only co-formulated protease inhibitor (PI), is approved for use in children
≥6 months of age at a dose of 230 mg/m2 twice daily, with a
maximum of 400 mg/dose. In adult PI-experienced patients, a target trough LPV
concentration of <5.7 mg/L has been associated with lower likelihood of viral
suppression. The aim of this study was to determine whether this target is relevant
in children, and achievable at the recommended pediatric dose.
Methods: Over
52 weeks, prospective data were collected from 50 HIV-infected PI-experienced
children (4 to 17 years old) receiving single PI-based therapy that included LPV/rtv.
Baseline drug susceptibility was measured (PhenoSense); HIV RNA viral load and
adherence (self-/family report) were measured at each study visit. At second
visit, pharmacokinetic blood samples were obtained immediately prior to
observed LPV intake, and at 30 minutes and 1, 2, 4, 8, and 12 hours after the
dose. LPV concentrations were measured by a published, validated tandem-mass
spectrometric method. By multiple logistic regression, trough LPV
concentration, adherence, and resistance were modeled as predictors of virologic
outcome (SAS). Pharmacokinetic data were fitted to candidate pharmacokinetic
models (USC*PACK software), and the model with the highest log-likelihood was
used to simulate 5000 children (ADAPT 5 software) to determine the percentage
with trough LPV concentration <5.7 mg/L after standard dosing.
Results: LPV
resistance (p = 0.003) and trough concentrations <5.7 (p = 0.03)
were significant predictors of never achieving viral load <400 copies/mL during
the study period. Adherence was not a significant predictor of virologic
outcome. The data from 35 patients were used to develop the pharmacokinetic
model, which was validated in the remaining 15 patients. The regression line of
the observed compared with the predicted LPV had an R2 of
0.98, a slope of 1.00, and an intercept of 0.08. LPV trough was <5.7 in 40%
of the 5000 children simulated from this model.
Conclusions: For PI-experienced children, an LPV
trough of <5.7 mg/L was significantly associated with sub-optimal virologic
response, independent of viral resistance and patient adherence. Furthermore, in
this validated pediatric population pharmacokinetic model of LPV/rtv, the currently
recommended dose of LPV will fail to consistently achieve this target in a large
percentage of children. Further studies on therapeutic drug monitoring of
LPV/rtv in children are warranted.
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