PK of efavirenz in children dosed according to WHO weight bands
Polly Clayden, HIV i-Base
Efavirenz (EFV) is used widely in children over 3 years old throughout the world. To date there is limited information about the steady state pharmacokinetics (PK) of EFV in African children.
A poster from Sabrina Bakeera-Kitaka and colleagues from the ARROW trial showed results from an investigation conducted to determine whether WHO recommended weight band dosing results in optimal EFV exposure in Ugandan children aged 3-12 years.
In this substudy, 41 HIV-positive children receiving generic EFV plus lamivudine (3TC) and abacavir (ABC) were enrolled in a crossover, PK study of twice vs once daily 3TC+ABC. This was conducted 36 weeks after the children started HAART in ARROW.
Children were dosed in accordance with WHO weight bands: 200/250/300*/350*mg for those weighing 1015, 1520, 2025, and 2530 kg respectively, using EFV capsules or *halved 600 mg tablets. Intensive sampling was performed at t=0, 1, 2, 4, 6, 8, and 12 hours post observed dose on twice-daily HAART at steady state and repeated 4 weeks later including a further 24 hour sample.
The investigators estimated EFV AUC0-24 and clearance (CL/kg) using WinNonlin, and predictors of log10AUC and CL were accessed using multivariate mixed models.
Of the children enrolled, 39 and 37 children had evaluable EFV profiles at the first and second PK sampling respectively.
The children were 41% (16/39) boys, 18 (46%) were aged 36 years and 21 (54%) 712 years. There were 5, 16, 15, and 3 children in the 1015, 1520, 2025 and 2530 kg weight-bands, respectively.
The investigators reported geometric mean (%CV) AUC0-24 of 50.4 (91.7%) and 54.0 (80.8%) h.mg/L at the first and second sampling respectively. They found no significant variation across weight-bands (p=0.51).
They noted a large inter- and intra-patient variability in EFV PK parameters (eg 81% and 28% for AUC0-24). They found 15% (6/39) children at the first sampling, and 7/37 at the second (7 children in total) had subtherapeutic C8hr and C12hr levels (<1.0mg/L); 38% (14/37) had therapeutic C24hr levels at the second sampling. They also found 23% (9/39) and 27% (10/37) children in the first and second sampling respectably (11 children in total) with a toxic C8hr and/or C12hr level (>4.0mg/L).
The investigators identified three groups of children using normal mixture modeling: 40% with geometric mean AUC0-24 27.2 h.mg/L, 32% with 49.9 h.mg/L and 28% with 137 h.mg/L. They suggested that genetic polymorphisms might play a role.
Mean clearance overall was 6.8 (SD 3.9) and 6.2 (3.7) L/h at the first and second sampling respectively (p =0.04). C/F increased by 0.50L/h for every year older (p=0.05), but was independent of weight (p=0.85), weight-for-age (p=0.52) or height-for-age (p=0.80).
Overall they found lower exposure than that previously reported in the tablets.
The ARROW group, are conducting ongoing investigations into the relationship between efavirenz concentrations and toxicity. The childrens viral loads will also be tested retrospectively. They wrote: Increasing the EFV dose for children should be investigated, and has been proposed by WHO. However higher proportions of children with toxic levels might be expected.
Ref: Natukunda E et al. Pharmacokinetics of efavirenz dosed according to the WHO weight-bands in children in Uganda. 17th CROI, 16-19 February 2010, San Francisco. Poster abstract 878.