Last year the Children with HIV in Africa -- Pharmacokinetics and Adherence of Simple ARV Regimens (CHAPAS)-2 trial found similar pharmacokinetics (PK) of a novel sprinkle formulation of lopinavir/ritonavir (LPV/r 40/10 mg per capsule from Cipla Pharmaceuticals) in Ugandan infants, compared to innovator syrup.
Acceptability data were also collected, showing most caregivers preferred the sprinkle formulation to the syrup for this age group1,2 A poster at CROI 2013 authored by Sabrina Kitaka and colleagues from CHAPAS-2 showed findings from the same comparison in children aged 1-4 years.3
This was an open label, crossover, PK trial in which children were dosed according to 2010 WHO weight bands guidelines. Four weeks after randomisation to syrup or sprinkles, samples were taken at 0, 1, 2, 4, 6, 8 and 12 hours after observed intake of LPV/r plus two NRTIs with food. After switching formulation, PK was repeated at week 8. Caregivers then chose which formulation to continue through 48 weeks of follow up and acceptability data were collected at each clinic visit.
LPV/r plasma concentrations were determined using high performance liquid chromatography. Comparisons in PK parameters were made between the two formulations.
A total of 26 children were enrolled with 46 evaluable PK profiles. All were already receiving LPV/r syrup for a median of 1.1 years (range 0.07-2.7). Twenty children had two evaluable PK profiles for within child sprinkle vs syrup comparisons. The children were a median age 2.0 years (IQR 1.8-2.8) and weight 10.7 kg (IQR 9.4-12.6) kg. Just over half (54%) were boys.
The evaluation revealed geometric mean (GM) of PK parameters of LPV sprinkles vs syrup:
|Sprinkes (95%CI)||Syrup (95%CI)||GMR (90%CI)|
|AUC0-12h (h.mg/L)||135.4 (115.5-158.8)||109.6 (93.3-128.6)||1.24 (1.08-1.42)|
|Cmax (mg/L)||14.9 (13.1-16.9)||12.6 (11.0-14.4)||1.18 (1.07-1.31)|
|C12h (mg/L)||6.22 (4.6-8.4)||4.42 (3.3-5.9)||1.41 (1.07-1.85)|
The investigators noted that LPV exposure with sprinkles was higher than with syrup and historical data for children aged 6 months - 12 years. There was moderately high variability (CV% 26 - 55%) in with both formulations but neither gave subtherapeutic levels (defined as <1.0 mg/L). Ritonavir PK was similar.
Most caregivers (58%) gave the sprinkles with porridge. Poor taste was reported most frequently as a problem with both formulations (38% sprinkles and syrup), followed by swallowing difficulty (27% sprinkles vs 19% syrup). At entry, 12% caregivers expected to prefer sprinkles, but at 12 weeks 67% preferred this formulation. At week 8, 73% caregivers chose to continue with sprinkles. Although 69% of caregivers rated both formulations unpleasant, they reported easier storage and transportation with sprinkles (0% problems) compared to syrup (54%). Independent scoring of administration showed no significant differences between the two formulations. Child refusal within the last week was reported by 19% with sprinkles and 12% with syrup.
Further PK and acceptability investigations are planned with an improved granule formulation with better taste masking.
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