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Lopinavir Population Pharmacokinetic Model and Dose Simulation Predicts Rapid Increase in Exposure for HIV-infected Infants Initiating Therapy at <6 Months of Age
Mina Nikanjam*1, E Capparelli1, B Robbins2, J Pinto3, C Alvero4, R Yogev5, P Palumbo6, M Hughes4, J Rodman7, E Chadwick5, and IMPAACT P1030 Team
1Univ of California, San Diego, US; 2Univ of Nebraska Med Ctr, Omaha, US; 3Federal Univ of Minas Gerais, Belo Horizonte, Brazil; 4Harvard Sch of Publ Hlth, Boston, MA, US; 5Northwestern Univ, Chicago, IL, US; 6Dartmouth Univ, Hanover, NH, US; and 7St Jude Children`s Res Hosp, Memphis, TN, US
Background: Lopinavir (LPV) apparent clearance has
been reported to be higher in young infants, thereby necessitating larger doses
to achieve adequate LPV exposure. We performed a population pharmacokinetic
analysis to characterize maturational changes in LPV pharmacokinetics and
assess dosing requirements.
Methods: LPV pharmacokinetic data were analyzed from
a prospective study, IMPAACT/PACTG P1030, which enrolled 31 HIV-infected
infants <6 months of age. Infants received LPV/ritonavir (RTV) 300/75 mg/m2
twice/day and 12-hour pharmacokinetic evaluations were performed after 2 weeks
of therapy, at 1 year of age, and following dose increases due to low LPV
levels. Trough LPV concentrations were obtained at regular intervals for up to
4 years. Pharmacokinetic analysis was performed on 549 LPV concentrations using
the program NONMEM and allometric scaling. Empiric post-hoc LPV pharmacokinetic
parameter estimates were generated from visits with multiple samples. Monte Carlo simulations were used to assess LPV dosing requirements.
Results: Age was a powerful predictor of LPV
apparent clearance (CL/F) and was best described as a nonlinear covariate for F
(bioavailability). Half-life was much less affected by age. Average RTV concentrations
predicted LPV CL/F. The inter-subject variability for CL/F and apparent volume
of distribution (V/F) were 27 and 40%. Median post hoc estimates from intensive
pharmacokinetic evaluations are shown in the table. Based on the model, LPV AUC
in a typical infant taking 300 mg/m2/dose reaches the adult value of
80 µg*h/mL by 9 months of age. The Monte Carlo simulations predicted frequency
of very low LPV troughs (<1 µg/mL) with 300 mg/m2 was 19% in
infants <3 months of age, but rare (<1%) in older infants. LPV troughs of
<3 µg/mL are expected in the majority of young infants <3 months, but
only in 14% of older infants. Using the new WHO weight-band dosing
recommendations, a lower frequency (11%) of troughs <1 µg/mL is predicted in
the youngest infants. :
|
|
CL/F (L/h/kg)
|
V/F (L/kg)
|
AUC (µg*h/mL)
|
|
Age <3 months n = 17
|
0.34
|
3.0
|
49.5
|
|
Age 3-6 months n = 19
|
0.22
|
2.2
|
66.6
|
|
Age ~1 year n = 26
|
0.13
|
1.3
|
109.5
|
Conclusions: LPV concentration increases during the
first year of life are likely due to increased bioavailability. A rapid
increase in LPV exposure likely accounts for the good virologic suppression
seen despite the low LPV concentrations present at the start of therapy in the
youngest infants. Frequent monitoring of LPV therapy in young infants is
warranted due to pharmacokinetic variability and the risk of low LPV exposure.
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