title: Need for therapeutic drug monitoring in HIV-1 infected children receiving efavirenz doses according to international guidelines.
abstract: BACKGROUND
  International guidelines for the treatment of HIV-1 infected children recommend efavirenz plus nucleoside reverse transcriptase inhibitor combination therapy for first line therapy. Until now little is known about the steady state pharmacokinetics of efavirenz in children.
  
  
  METHODS
  11 HIV-1 infected children at the age of 4 to 10 years received efavirenz according to body weight adjusted dose recommendations at 10 -15 mg/kg body weight. All children were non nucleoside reverse transcriptase inhibitor (NNRTI) naive, 5/11 received efavirenz as first line therapy. Efavirenz plasma concentrations were assessed before daily dose and 1, 2, 4, 8, 24 h post-dose after medication by established HPLC.
  
  
  RESULTS
  7 of 11 children exhibited efavirenz plasma concentrations below targeted ranges. Mean (95% CI) minimum concentrations (C subsetmin) was 1293 ng/mL (range: 889 -1697) and maximum concentration (C subsetmax) was 5552 ng/mL (3951 - 7153) and the mean area under the time-concentration curve at steady state (AUCss) was 63608 ng*h/mL (44222 - 82989). The linear regression analysis of bodyweight adjusted efavirenz AUCss showed a close correlation between dose/bodyweight and plasma concentrations (r superset2 = 0.79). Efavirenz doses below 12.5 mg/kg lead to an AUC < 60000 ng*h/mL in 7 of 8 cases. Higher efavirenz doses exhibited an AUC within the recommended therapeutic range of 60000 - 120000 ng*h/mL (n = 3).
  
  
  CONCLUSIONS
  The data show insufficient plasma concentrations for some children despite efavirenz dosing according to recommendations. Antiretroviral therapy needs to be carefully adjusted in children. Therapeutic drug monitoring is strongly recommended to meet efavirenz plasma levels within the therapeutic range.
authors.affiliation: Institute for Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, J.W.Goethe University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. Hentig@em.uni-frankfurt.de
authors.forename: Nils
authors.initials: N
authors.lastname: von Hentig
authors.forename: C
authors.initials: C
authors.lastname: Koenigs
authors.forename: S
authors.initials: S
authors.lastname: Elanjikal
authors.forename: R
authors.initials: R
authors.lastname: Linde
authors.forename: D
authors.initials: D
authors.lastname: Dunsch
authors.forename: W
authors.initials: W
authors.lastname: Kreuz
authors.forename: M B
authors.initials: MB
authors.lastname: Funk
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D048588:Benzoxazines; D002648:Child; D002675:Child, Preschool; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007390:International Agencies; D008297:Male; D010078:Oxazines / Q000627:therapeutic use*; D017410:Practice Guidelines as Topic
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; C098320:efavirenz