Efavirenz under-dosing in children
Polly Clayden HIV i-Base
An article in the December 1 2011 edition of JAIDS describes efavirenz (EFV) exposure in African children in the ARROW trial, dosed according to the 2006 WHO weight bands, which are similar to the manufacturer’s recommendations (the current approved paediatric doses).
ARROW is an open label randomised trial comparing routine laboratory to clinical monitoring (a paediatric version of DART) in children in Uganda and Zimbabwe. It also compares different ART strategies. Quirine Fillekes and colleagues from the trial team conducted a pharmacokinetic (PK) sub study in Ugandan children aged 3-12 years. The children evaluated had received twice daily lamivudine plus abacavir (3TC+ABC) with once daily EFV and participated in a crossover study comparing twice to once daily 3TC+ABC.
EFV was dosed according to WHO 2006 weight bands. Doses were 200, 250, 300 and 350 mg for children weighing 10 to <15, 15 to <20, 20 to <25 and 25 to >30 kg respectively. The children received 200/50mg capsules or halved 600mg tablets.
At week 36 from initiating treatment (once daily EFV plus NRTIs), 12 hour PK sampling was performed, pre-dose and at 1, 2, 4, 6, 8 and 12 hours post dose. The children were switched to once daily NRTIs at 36 weeks. Intensive PK sampling was repeated at 40 weeks, including an extra PK sample at 24 hours post dose.
A total of 41 (24 girls and 17 boys) were enrolled in this sub study. Of these, 4 children increased weight bands between the first and second PK sampling but were included in the analyses and 2 were excluded due to implausible time concentration curves (believed to be labeling errors).
Eighteen of the children were age 3 to 6 years and 23 children were 7 to 12 years. The majority were moderately stunted and wasted. Five, 16, 17 and 3 children were in the 10 to <15, 15 to <20, 20 to <25 and 25 to >30 kg weight bands respectively, at the first PK sampling.
Doses in mg/kg were highest in the 15 to <20 kg (median 14.7 mg/kg) and lowest in the 20 to <25 kg (median 13.0 mg/kg) weight bands. The median dose received overall was 13.6mg/kg.
The geometric mean EFV plasma concentrations time curves obtained at the first and second samplings were similar. Six children at the first sampling and 7 children at the second had subtherapeutic (<1.0 mg/L) plasma concentrations at 8 hours and/or at 12 hours; 7/41 (17%) at either sampling. At the second sampling 15/39 (38%) of children had subtherapeutic levels at 24 hours. Ten (24%) children at the first sampling and 11 (28%) at the second had potentially toxic levels >4 mg/L at 8 hours and/or at 12 hours; 12/41 at either sampling.
Overall the EFV Cmax, Cmin and AUC0-24 were respectively 15%, 36% and 10% lower than those observed in adults receiving the 600mg tablet.
The authors observed wide intersubject but modest intrasubject variability across EFV PK parameters. There was no evidence of significant differences across the four weight bands for all PK parameters evaluated (suggesting no major effect of using divided tablets) however, with only 41 children in total the sub study was rather underpowered to show this.
They wrote that these data (and that of two previous studies) strongly suggest that children should receive EFV doses higher than the WHO 2006 recommendations or the manufacturers daily dose in the leaflet (50mg higher only for children weighing 14 to <15 kg and 30 to 32.5 kg).
More recent 2010 dosing guidelines have higher EFV doses than evaluated in this study for children weighing 14 to <20, 25 to <30 and 35 to <40 kg. The authors noted that these higher doses were not only selected in response to concerns about under doing but to remove the 50 mg tablets from dosing tables as these were being discontinued.
They expressed concern that although these data suggest that higher doses should lead to greater exposure and in turn better virological efficacy, the trade off is that more than one-third of children will be exposed to potentially toxic EFV levels.
Fillekes Q et al. pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda. J Acquir Immune Defic Syndr. Volume 58. Number 4. December 1, 2011.