title: Pharmacokinetics and 48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency Virus Type-1-Infected Children 4 Weeks to 2 Years of Age.
abstract: BACKGROUND
  IMPAACT P1066 is a Phase I/II open-label multicenter trial to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple raltegravir (RAL) formulations in human immunodeficiency virus (HIV)-infected youth.
  
  
  METHODS
  Dose selection of the oral suspension formulation for each cohort (IV: 6 months to <2 years and V: 4 weeks to <6 months) was based on review of short-term safety (4 weeks) and intensive PK evaluation. Safety data through Weeks 24 and 48 and Grade ≥3 or serious adverse events (AEs) were assessed. The primary virologic endpoint was achieving HIV RNA <400 copies/mL or ≥1 log10 reduction from baseline at Week 24 (Success). For Cohort IV, optimized background therapy (OBT) could have been initiated with RAL either at study entry or after intensive PK sampling was completed at Day 5-12. An OBT was started when RAL was initiated for Cohort V subjects because they were not permitted to have received direct antiretroviral therapy before enrollment.
  
  
  RESULTS
  Total accrual was 27 subjects in these 2 cohorts, including 1 subject who was enrolled but never started study drug (excluded from the analyses). The targeted PK parameters (area under the curve [AUC]0-12hr and C12hr) were achieved for each cohort allowing for dose selection. Through Week 48, there were 10 subjects with Grade 3+ AEs. Two were judged related to study drug. There was 1 discontinuation due to an AE of skin rash, 1 event of immune reconstitution syndrome, and no drug-related deaths. At Week 48, for Cohorts IV and V, 87.5% of subjects achieved virologic success and 45.5% had HIV RNA <50 copies/mL. At Week 48, gains in CD4 cells of 527.6 cells/mm(3) and 7.3% were observed.
  
  
  CONCLUSIONS
  A total of 6 mg/kg per dose twice daily of RAL for oral suspension was well tolerated and showed favorable virologic and immunologic responses.
authors.affiliation: Health Sciences Center, SUNY Stony Brook, Pediatrics, New York.
authors.forename: Sharon
authors.initials: S
authors.lastname: Nachman
authors.affiliation: Harvard School of Public Health, Statistical and Data Analysis Center, Boston, Massachusetts.
authors.forename: Carmelita
authors.initials: C
authors.lastname: Alvero
authors.affiliation: University of Alabama at Birmingham.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.affiliation: Merck & Co, West Point, Pennsylvania.
authors.forename: Hedy
authors.initials: H
authors.lastname: Teppler
authors.affiliation: Merck & Co, West Point, Pennsylvania.
authors.forename: Brenda
authors.initials: B
authors.lastname: Homony
authors.affiliation: Frontier Science and Technology Research Foundation, Buffalo, New York.
authors.forename: Bobbie
authors.initials: B
authors.lastname: Graham
authors.affiliation: Harvard School of Public Health, Statistical and Data Analysis Center, Boston, Massachusetts.
authors.forename: Terence
authors.initials: T
authors.lastname: Fenton
authors.affiliation: Merck & Co, West Point, Pennsylvania.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Merck & Co, West Point, Pennsylvania.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Rizk
authors.affiliation: University of California San Diego, Rady Children's Hospital San Diego, La Jolla, California.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Spector
authors.affiliation: Seattle Children's Hospital, Center for Childhood Infections, Washington.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Frenkel
authors.affiliation: Maternal and Pediatric Infectious Diseases Branch, Eunice Kennedy Shriver National Institute of Child, Health and Human Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Carol
authors.initials: C
authors.lastname: Worrell
authors.affiliation: Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.
authors.forename: Edward
authors.initials: E
authors.lastname: Handelsman
authors.affiliation: Jacobi Medical Center, Pediatrics, Bronx, New York.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wiznia
mesh_terms: D000284:Administration, Oral; D002675:Child, Preschool; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1; D006801:Humans; D007223:Infant; D008297:Male; D000068898:Raltegravir Potassium / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*
chemical_list: D000068898:Raltegravir Potassium
keywords: pediatric HIV; raltegravir; treatment