PMID- 26582887 OWN - NLM STAT- MEDLINE DCOM- 20171025 LR - 20190924 IS - 2048-7207 (Electronic) IS - 2048-7193 (Print) IS - 2048-7193 (Linking) VI - 4 IP - 4 DP - 2015 Dec TI - 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. PG - e76-83 LID - 10.1093/jpids/piu146 [doi] AB - 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. CI - (c) The Author 2015. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com. FAU - Nachman, Sharon AU - Nachman S AD - Health Sciences Center, SUNY Stony Brook, Pediatrics, New York. FAU - Alvero, Carmelita AU - Alvero C AD - Harvard School of Public Health, Statistical and Data Analysis Center, Boston, Massachusetts. FAU - Acosta, Edward P AU - Acosta EP AD - University of Alabama at Birmingham. FAU - Teppler, Hedy AU - Teppler H AD - Merck & Co, West Point, Pennsylvania. FAU - Homony, Brenda AU - Homony B AD - Merck & Co, West Point, Pennsylvania. FAU - Graham, Bobbie AU - Graham B AD - Frontier Science and Technology Research Foundation, Buffalo, New York. FAU - Fenton, Terence AU - Fenton T AD - Harvard School of Public Health, Statistical and Data Analysis Center, Boston, Massachusetts. FAU - Xu, Xia AU - Xu X AD - Merck & Co, West Point, Pennsylvania. FAU - Rizk, Matthew L AU - Rizk ML AD - Merck & Co, West Point, Pennsylvania. FAU - Spector, Stephen A AU - Spector SA AD - University of California San Diego, Rady Children's Hospital San Diego, La Jolla, California. FAU - Frenkel, Lisa M AU - Frenkel LM AD - Seattle Children's Hospital, Center for Childhood Infections, Washington. FAU - Worrell, Carol AU - Worrell C AD - Maternal and Pediatric Infectious Diseases Branch, Eunice Kennedy Shriver National Institute of Child, Health and Human Development, National Institutes of Health, Bethesda, Maryland. FAU - Handelsman, Edward AU - Handelsman E AD - Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland. FAU - Wiznia, Andrew AU - Wiznia A AD - Jacobi Medical Center, Pediatrics, Bronx, New York. LA - eng GR - UM1 AI068616/AI/NIAID NIH HHS/United States GR - UM1 AI069456/AI/NIAID NIH HHS/United States GR - UM1AI068616/AI/NIAID NIH HHS/United States GR - M01 RR016587/RR/NCRR NIH HHS/United States GR - UM1 AI106716/AI/NIAID NIH HHS/United States GR - UL1 TR001427/TR/NCATS NIH HHS/United States GR - UL1 RR029890/RR/NCRR NIH HHS/United States GR - UM1 AI068632/AI/NIAID NIH HHS/United States GR - UM1AI068632/AI/NIAID NIH HHS/United States GR - UM1AI106716/AI/NIAID NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150207 PL - England TA - J Pediatric Infect Dis Soc JT - Journal of the Pediatric Infectious Diseases Society JID - 101586049 RN - 43Y000U234 (Raltegravir Potassium) SB - IM MH - Administration, Oral MH - Child, Preschool MH - Female MH - HIV Infections/*drug therapy MH - HIV-1 MH - Humans MH - Infant MH - Male MH - Raltegravir Potassium/administration & dosage/*pharmacokinetics/*therapeutic use PMC - PMC4681385 OTO - NOTNLM OT - pediatric HIV OT - raltegravir OT - treatment EDAT- 2015/11/20 06:00 MHDA- 2017/10/27 06:00 PMCR- 2016/12/01 CRDT- 2015/11/20 06:00 PHST- 2014/10/21 00:00 [received] PHST- 2014/12/28 00:00 [accepted] PHST- 2015/11/20 06:00 [entrez] PHST- 2015/11/20 06:00 [pubmed] PHST- 2017/10/27 06:00 [medline] PHST- 2016/12/01 00:00 [pmc-release] AID - piu146 [pii] AID - 10.1093/jpids/piu146 [doi] PST - ppublish SO - J Pediatric Infect Dis Soc. 2015 Dec;4(4):e76-83. doi: 10.1093/jpids/piu146. Epub 2015 Feb 7.