Pediatric underdosing of efavirenz: a pharmacokinetic study in Uganda

OBJECTIVES: To evaluate international pediatric efavirenz dosing recommendations using full pharmacokinetic (PK) information. DESIGN: Open-label, multicenter, PK study. METHODS: Forty-one HIV-infected Ugandan children (3-12 years) on efavirenz + lamivudine + abacavir were enrolled in a study of twice-daily to once-daily lamivudine + abacavir 36 weeks after antiretroviral therapy initiation in the ARROW trial. Once-daily efavirenz doses were 200, 250, 300, 350 mg for children weighing 10 to 4.0 mg/L; 12 of 41 (29%) at either visit. CONCLUSIONS: African children aged 3-12 years, on efavirenz dosed according to 2006 WHO/manufacturer's recommendations, had lower and highly variable efavirenz PK parameters compared with adult data from manufacturer's leaflet. There were no differences across weight bands, suggesting no major effect of using half tablets. Higher pediatric efavirenz doses, as per WHO 2010 recommendations, should be used and investigated further but may risk increasing the proportion of children with potentially toxic levels.