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Pharmacokinetic (PK), Safety and Efficacy Data on Cohort IIA; youth aged 6-11 from IMPAACT P1066: A Phase I/II Study to Evaluate Raltegravir (RAL) in HIV-1 Infected Youth
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Reported by Jules Levin
CROI 2010 Feb 16-19 SF
S. NACHMAN1, E Acosta2, Pearl Samson3, Hedy Teppler4, Brenda Homony4, Terry Fenton3, Ed Handelsman5, Carol Worrell6, Bobbie Graham7, Andrew Wiznia8
1SUNY Stony Brook, NY, 2U Alabama, AL 3Harvard School Public Health, MA, 4 Merck, PA, 5 NIAID, MD, 6NICHD, MD, 7 Frontier Science Research Foundation Inc., NY, 8 Jacobi Med Center, NY
ABSTRACT
Background: RAL is a potent selective HIV-1 integrase inhibitor approved for use in adults. P1066 is a study of open label RAL in treatment experienced HIV+ youth. PK, safety and efficacy data in HIV+ youth 12-18 (cohort I) were recently reported. Here we report PK, 12 week (wk) antiretroviral activity and all available safety data through September 14, 2009 from cohort IIA, 6-11 year-old participants placed on RAL tablets.
Methods: HIV+ youth enrolled in Stage 1: dose finding with intensive PK, safety and wk 12 efficacy. Entry criteria included HIV RNA>1000 copies/mL, treatment experienced but naïve to integrase inhibitors, and excluded patients with HBV or HCV. Intensive PKs were completed between days 5 and 12 for all 14 subjects enrolled. ARV were optimized after intensive PKs completed. After PK were examined, a dose for continued study was selected. Success was defined as achieving and maintaining >1-log drops from baseline or viral loads of ≤400 copies/ml and on-study treatment at study specified dose at wk 12. Any patients taken off-treatment prior to wk 12 were considered failures. vRNA <50 also examined. All patients were included in the safety analyses
Results: Baseline demographics: Male: 60%; Race: 90% Black/African American, Median: weight=30kgs; age=9yrs; log10RNA=4.4 CD4=536. Week 12 efficacy (Intent to Treat) data is available on 8 patients. Subjects dosed at 8 mg/kg (200, 300 or 400 mg) showed a geometric mean (GM) AUC 12 of 14.8 μMxh (2.3-111) allowing for selection of 400 mg BID of adult formulation tablets as a final dose. Subjects weighing less than 25kg were placed on alternative formulations. Repeat PKs were done on all subjects at 400 mg BID which revealed a GM AUC 12 of 15.8 μMxh (1.6-111). At 400 mg BID the GM trough and Cmax were 246 nM and 4.8μM. There were three grade 3 adverse events, 1 possibly related (low ANC). No treatment discontinuations were due to adverse events. At 12 wks, 75% achieved success, 95%CI [35%, 97%]; 62% achieved <50 copies/mL, 95%CI [24%, 91%]. Success was similar to previously reported data on the 12-18 year old study cohort
Conclusions: A RAL dose of 400 mg BID of the adult formulation was chosen for continued study in HIV infected youth ages 6-11 and at least 25 kg in weight. In these subjects, RAL appears generally safe and well tolerated through wk 12, and achieved efficacy rates comparable to those in treatment experienced youth aged 12-18 and adults.
400 mg BID dose was picked based on all available data including PK at 8 mg/kg, AUC12 PK data, weight bands and Cohort I results.
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