title: Efavirenz Capsule Sprinkle and Liquid Formulations With Didanosine and Emtricitabine in HIV-1-infected Infants and Children 3 Months to 6 Years of Age: Study AI266-922.
abstract: BACKGROUND
  AI266-922 was an open-label, dose-ranging study that assessed the pharmacokinetics, safety and efficacy of efavirenz (EFV) in children (3 months to 6 years).
  
  
  METHODS
  Antiretroviral-naïve and antiretroviral-experienced HIV-1-infected children received once-daily EFV as oral solution or capsule sprinkle plus didanosine and emtricitabine (FTC). Pharmacokinetic analyses were undertaken at week 2 and repeated at weeks 10 and 18 after an EFV dose change or switch from oral solution to capsule sprinkle.
  
  
  RESULTS
  Thirty-seven subjects were treated. EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose values were generally suboptimal (<110 μM × h) in subjects younger than 3 years treated with oral solution; these subjects switched to capsule sprinkle. Twenty of 21 subjects younger than 3 years treated with capsule sprinkle achieved an EFV area under the plasma concentration-time curve over 1 dosing interval from time 0 to 24 hours postdose value >110 μM × h, although higher initial doses were administered in this age group. Interpatient variability in EFV exposure was high. By week 48, 77.8% and 63.0% of subjects achieved HIV-RNA <400 and <50 copies/mL, respectively. Median changes in log10 HIV-RNA and CD4 percentage from baseline were -3.18 copies/mL and +6%, respectively. Two (5.4%) patients discontinued because of adverse events (AEs). Serious AEs occurred in 20 (54.1%) subjects. Common AEs were diarrhea (49%), nasopharyngitis (35%) and pneumonia (30%). Overall, 43% of subjects with suboptimal EFV exposure at week 2 developed resistance.
  
  
  CONCLUSIONS
  Once-daily EFV, given as capsule sprinkle, achieved target exposures in this study although doses were 2-3 times higher than Food and Drug Administration-approved doses for children younger than 3 years. These data are useful for dose selection modeling and simulation; however, Food and Drug Administration-approved doses should be used clinically. EFV + didanosine + FTC was efficacious with no new pediatric safety findings reported.
authors.affiliation: From the *Hospital Infantil de México Federico Gomez, México City, México; †Family Clinical Research Unit, Tyberberg Children's Hospital, Cape Town, South Africa; ‡Universidad Panamá School of Medicine, Hospital del Niño de Panamá, Panama City, Panamá; §HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross AIDS Research Centre (TRCARC), Bangkok, Thailand; ¶Bristol-Myers Squibb, Wallingford, Connecticut; ‖Bristol-Myers Squibb, Hopewell, New Jersey; and **Bristol-Myers Squibb, Plainsboro, New Jersey.
authors.forename: Noris
authors.initials: N
authors.lastname: Pavia-Ruz
authors.forename: Magdel
authors.initials: M
authors.lastname: Rossouw
authors.forename: Xavier
authors.initials: X
authors.lastname: Sáez-Llorens
authors.forename: Torsak
authors.initials: T
authors.lastname: Bunupuradah
authors.forename: Mathew
authors.initials: M
authors.lastname: Taylor
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Heather
authors.initials: H
authors.lastname: Sevinsky
authors.forename: Mark
authors.initials: M
authors.lastname: Krystal
authors.forename: Max
authors.initials: M
authors.lastname: Lataillade
authors.forename: Daniel
authors.initials: D
authors.lastname: Seekins
authors.forename: Sophie
authors.initials: S
authors.lastname: Biguenet
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002675:Child, Preschool; D003521:Cyclopropanes; D016049:Didanosine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068679:Emtricitabine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D000068679:Emtricitabine; C098320:efavirenz; D016049:Didanosine