TUAB0203 - Oral Abstract
Pharmacokinetics, safety and efficacy of dolutegravir (DTG; S/GSK1349572) in HIV-1-positive adolescents: preliminary analysis from IMPAACT P1093
Presented by Rohan Hazra (United States).
R. Hazra1, R. Viani2, E. Acosta3, N. Zheng4, C. Alvero4, E. O'Gara5, E. Petzold6, B. Heckman7, D. Steimers8, I. Song8, S. Piscitelli8, A. Wiznia9, P1093 Study Team
1NIH/NICHD, Pediatric Adolescent and Maternal AIDS Branch, Bethesda, United States, 2University of California San Diego School of Medicine, La Jolla, United States, 3University of Alabama at Birmingham School of Medicine, Birmingham, United States, 4Harvard School of Public Health, Boston, United States, 5NIH/NIAID, International Maternal, Adolescent and Pediatric Branch, Bethesda, United States, 6Social & Scientific Systems, Durham, United States, 7Frontier Science and Technology Research Foundation, Inc., Amherst, United States, 8GlaxoSmithKline, Research Triangle Park, United States, 9Jacobi Medical Center, Bronx, United States
Background: P1093, is an ongoing, Phase 1/2 open-label PK, safety dose finding study of DTG plus optimized background regimen (children 6 wks to < 18 yrs) in age defined cohorts. Selected pediatric doses will be those providing comparable PK exposure to those observed at 50mg once daily in adults with acceptable pediatric safety/tolerability.
Methods: Children >12 to < 18 yrs were enrolled to evaluate DTG weight-based fixed doses at ~1.0 mg/kg once daily. Intensive PK evaluation, over 24 hours, following observed dose (Days 5-10) after DTG was added to stable, failing ARV regimen (or started as monotherapy, those not currently taking ARV). Background therapies were optimized immediately following completion of intensive PK. Safety, tolerability, HIV RNA assessments were performed (Week 4 and every 4 weeks throughout). Target PK exposures were AUC(0-24) range of 37-67 mg*h/mL (primary) and C24 range 0.77 - 2.26 mg/ml (secondary).
Results: Ten adolescents (7 female) with mean (SD) age 14 yrs (1.89) and weight 57.3 kg (17.7) were enrolled. Nine subjects received DTG 50mg and 1 subject received DTG 35mg daily. Median Baseline (BL) CD4+ cell % and HIV-1 RNA log10 were 21.5% (IQR:18.4-26) and 4.40 log10 copies/mL (IQR:4.17-4.84), respectively. DTG demonstrated moderate intersubject PK variability; geometric mean (CV%) AUC(0-24) and C24 were 46.0 (43%) mg*h/ml and 0.90 (58%)mg/mL, respectively. HIV-1 RNA < 40 c/mL was achieved (7/10 subjects (70%)) after 4 weeks of dosing; median change from BL was -2.8log10copies/mL (95% CI: -3.1, -2.6). DTG was generally well tolerated, with one Grade 3, no Grade 4 AEs, no discontinuations due to AEs, no trends in lab abnormalities.
Conclusions: Preliminary data suggest DTG achieved target mean AUC(0-24) and C24 in children >12 to < 18 years. DTG plus OBT was generally well tolerated (Week 4). Data support further DTG investigation at selected dose, and younger pediatric cohort initiation.
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