Pediatric Formulations of ARVs: Including an Exciting New Class
The integrase inhibitor raltegravir (RAL) is approved as a 400 mg film-coated tablet for use in adults and for children aged 6 to 18 weighing > 10 kg, and 100 mg and 25 mg chewable tablets are approved for children > 2 to <12 years old at a maximum dose of 300 mg. 
The paediatric programme is ongoing in IMPAACT P1066 and an oral granule formulation is being studied in the youngest children and babies. Stephen Spector and colleagues from the study team presented intensive PK, and preliminary 24 weeks safety and efficacy data from cohort IV -- 6-month- to <2-year-olds -- receiving the RAL oral granule formulation. 
Nine HIV-infected children were enrolled in a dose-finding study. Entry criteria included HIV RNA >1000 copies/mL and either prior ART experience PMTCT failure. The children received weight-based RAL oral granule suspension at ~6 mg/kg, every 12 hours.
Intensive PK was performed between day 5 and 12 after which the site investigators optimised the children's background regimen. A dose was selected for continued study using an AUC12 hr targeted design (geometric mean [GM] target range of 14 to 25 uM*h) with C12h target to exceed the RAL IC95 (31 nM). Virologic suppression was defined as HIV RNA <400 copies/mL or >1 log drop from baseline at 24 weeks.
One child's PK data were excluded due to absorption issues. Of the remaining 8 children: 67% were male; 78% black; mean (SD) age, 13 months (6.3); log10 RNA, 5.68 copies/mL (0.95); CD4 percent, 21% (9%); CD4 count, 1338 cells (822); weight, 8.3 kg (2.6), dose, 5.94 mg/kg (0.42).
The investigators reported geometric mean values of: AUC12hr, 20 uM*h; Cmax, 10.7 uM; and C12h, 115 nM. These PK values are achieved study targets and are similar to those observed in 2 to < 12 year old children receiving chewable tablets. Of the 9 children enrolled, 3 had 16 grade >3 adverse events of which 2 were considered related to RAL.
One child had grade 1 spitting up after taking the study drug.
At week 12, 78% (95% CI 40 to 97%) of the 9 children achieved virologic suppression. The children had a median gain in CD4 percent of 5% (95% CI 3 to 7%) and CD4 cells of 687 (95% CI 297 to 1237) cells/mm3 at week 12. By 24 weeks (n=7), 85% achieved virologic suppression and CD4 gain (n=8) was 5.3% (95% CI -4.0 to 18.8%) and 446 (95% CI 13 to 696) cells/mm3.
The 6 mg/kg every 12 hours dose was chosen for continued study in this age group.
A sprinkle formulation of lopinavir/r (LPV/r) Lopimune -- has been in development by the generic manufacturer Cipla for some time. The sprinkle formulation (40/10 mg LPV/r) consists of a finite number of mini tablets in a capsule, which is opened and sprinkled on soft food.
Jaideep A Gogtay and colleagues showed results from a randomised crossover PK study in healthy adults comparing a single dose of sprinkles from 10 capsules of LPV/r and a single dose of 5 mL Kaletra oral solution (each mL containing 80 mg lopinavir and 20 mg ritonavir).
Both formulations were administered with about 150 g porridge and 240 mL water. Blood samples were taken pre-dose and serially up to 36 hours and were analysed using a validated LCMS/MS method. PK parameters were calculated using a non-compartmental method using drug concentrations versus time profile.
Twelve subjects completed the study (ie the minimum sample size acceptable to regulatory authorities). Their PK parameters are shown in Table 2.
For LPV the Ln-transformed 90% confidence interval of the least square mean of the LPV/r sprinkles and solution for the PK parameters AUC0-t and AUC 0-IFN fall within the conventional bioequivalence range of 80 -125% while for Cmax it falls just outside. For RTV AUC0-t and Cmax fall just outside the range but AUC 0-∞ falls within it. However, the investigators noted that the differences were not large. Based on this pilot PK study, the sprinkle formulation is now being studied in HIV-infected children.
This article was provided by HIV i-Base. It is a part of the publication HIV Treatment Bulletin. Visit HIV i-Base's website to find out more about their activities, publications and services.
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