title: Pediatric underdosing of efavirenz:  a pharmacokinetic study in Uganda.
abstract: OBJECTIVE
  To evaluate international pediatric efavirenz dosing recommendations using full pharmacokinetic (PK) information.
  
  
  METHODS
  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 postobserved 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 postdose 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 C(8h) and/or C(12h) (<1.0 mg/L), 7 of 41 (17%) at either visit. At PK2, 15 of 39 (38%) children had C(24h) <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 C(8h) and/or C(12h) >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.
authors.affiliation: Department of Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. Q.Fillekes@akf.umcn.nl
authors.forename: Quirine
authors.initials: Q
authors.lastname: Fillekes
authors.forename: Eva
authors.initials: E
authors.lastname: Natukunda
authors.forename: Jackie
authors.initials: J
authors.lastname: Balungi
authors.forename: Lindsay
authors.initials: L
authors.lastname: Kendall
authors.forename: Mutsa
authors.initials: M
authors.lastname: Bwakura-Dangarembizi
authors.forename: Rosette
authors.initials: R
authors.lastname: Keishanyu
authors.forename: Alex
authors.initials: A
authors.lastname: Ferrier
authors.forename: Joseph
authors.initials: J
authors.lastname: Lutakome
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
authors.forename: David M
authors.initials: DM
authors.lastname: Burger
authors.forename: A Sarah
authors.initials: AS
authors.lastname: Walker
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D015224:Dideoxynucleosides / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage; D008297:Male; D014454:Uganda; D000099227:Abacavir
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D015224:Dideoxynucleosides; D004338:Drug Combinations; D019259:Lamivudine; C492871:abacavir, lamivudine drug combination; D000099227:Abacavir; C098320:efavirenz