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
15, 15 to 20, 20 to 25, 25 to 30 kg, respectively, using 200/50 mg
capsules or halved 600 mg tablets in case of 300 and 350 mg doses.
Intensive plasma PK sampling (t = 0, 1, 2, 4, 6, 8, 12 hours
post-observed ingestion) was performed at steady state (PK1) and
repeated 4 weeks later (PK2, including a further 24-hour sample).
Results: Forty-one and 39 children had evaluable efavirenz profiles at
PK1 and PK2, respectively. Seventeen (41%) were boys. Five, 16, 17, 3
were in the 10 to 15, 15 to 20, 20 to 25, 25 to 30 kg weight bands. The
geometric mean (%CV) the area under the concentration–time curve 0–24
hours post-dose was 50.8 (90.8%) and 55.5 (82.7%) h·mg·L-1 at PK1 and
PK2, respectively. Six children at PK1 and 7 at PK2 had subtherapeutic
C8h and/or C12h (less than 1.0 mg/L), 7 of 41 (17%) at either visit. At
PK2, 15 of 39 (38%) children had C24h less than 1.0 mg/L (median
(interquartile range) [range] 1.1 (0.7–2.9) [0.3–18.4]). Ten
children at PK1 and 11 at PK2 had C8h and/or C12h less than 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.
Fillekes, Q.; Natukunda, E.; Balungi, J.; Kendall, L.; Bwakura-Dangarembizi, M.; Keishanyu, R.; Ferrier, A.; Lutakome, J.; Gibb, D.M.; Burger, D.M.; Walker, A.S. Pediatric Underdosing of Efavirenz: A Pharmacokinetic Study in Uganda. Journal of Acquired Immune Deficiency Syndromes (2011) 58 (4) 392-398. [DOI: 10.1097/QAI.0b013e318235e560]
Pediatric Underdosing of Efavirenz: A Pharmacokinetic Study in Uganda