WHO updated the guidelines for paediatric weight band dosing of efavirenz (EFV) in 2010. The generic manufacturer Cipla has developed scored 600 mg EFV tablets to facilitate appropriate weight band dosing.
These tablets are scored once on one side and twice on the other to provide 300 mg, 200 mg and 400 mg divided doses.
Children with HIV in Africa -- Pharmacokinetics and Adherence/Acceptability of Simple Antiretroviral Regimens (CHAPAS-3) is an open-label three centre randomised phase 2/3 trial evaluating new solid, dispersible scored antiretroviral fixed dose combination (FDC) and single agents in African children.1
Children, weighing 10- to <20kg and receiving the generic double-scored EFV tablets in a regimen with new generic combination tablets of 3TC/abacavir(ABC) or 3TC/AZT were enrolled in a pharmacokinetic (PK) sub-study.
In accordance with the new guidelines, the once-daily EFV doses were 200 mg and 300 mg for those weighing 10 to <14 kg and 14 to <20 kg, respectively. Intensive 24 hour PK sampling was performed 6 weeks after ART initiation. Samples were obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours. AUC0-24, Cmax and C24h levels were analysed.
The substudy enrolled 31 Ugandan/Zambian children of which, 29 efavirenz profiles were evaluable: 11 in the 10 to <14 kg and 18 in the 14 to <20 kg weight bands. Just under half (43%) were girls and the children were a median of 4.6 ( IQR 3.9-5.0) years of age.
The investigators reported, the geometric mean (95%CI) AUC0-24 was 46.5(29.4-73.6) and 49.7(30.9-79.9)h*mg/L for weight-band 10 to <14 and 14 to <20kg respectively, compared to 58 h.mg/L in adults.
They observed a large variability in the EFV PK parameters with CV% 133%, 104% and 156% for AUC0-24h, Cmax and C24h, respectively. However, they did not find significant variation between the two weight bands, p= >0.6.
EFV parameters were approximately 15% lower than those previously reported in adults receiving 600 mg once daily. But they were similar to those previously reported in children dosed according to the 2006 WHO guidelines: 200 mg for 10 to <14 kg and 250 mg for 14 to <20 kg once daily. See Table 1.
|Table 1: PK Oarameters of EFV Including Historical Comparisons|
|EFV||10 to <14 kg||14 to < 20 kg||Literature Data Children||Literature Data Adults|
|C24h (mg/L)||1.29(0.75 - 2.20)||1.37(0.77 - 2.43)||1.36(1.00 - 1.85)||1.77(1.01)|
|Cmax (mg/L)||2.94(2.07 - 4.19)||3.42(2.32 - 5.04)||3.5(2.86 - 4.29)||4.07(1.16)|
|AUC0-24h (mg/L.h)||46.5(29.4 - 73.8)||49.73(31.0 - 79.9)||54.0(42.6 - 68.4)||58.08(23.04)|
Geometric mean (95% CI) and arithmetic mean (SD) for adult data.
The investigators also observed a high number of sub-therapeutic (<1.0 mg/L) and supra-therapeutic (>4.0 mg/L) levels -- these did not differ between weight bands, p=0.87. See Table 2.
|Table 2: EFV Concentrations After Observed Intake|
|Time After Intake (Hours)||Weight Band (kg)||< 1.0 mg/L||> 4.0 mg/L|
|8 and/or 12||10 to <14||9%||27%|
|14 to < 20||22%||28%|
|24 hours||10 to <14||55%||18%|
|14 to < 20||67%||22%|
The investigators wrote: "This study demonstrates the challenges of fixed dosing when the therapeutic range is narrow."
Evaluation of EFV PK in higher weight bands (20 to <30 kg) is ongoing as is evaluation of toxicity, efficacy and acceptability of the new EFV tablet.
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