Raltegravir Oral Granules Formulation in Children 6 months to <2 Years of Age: Interim Results from IMPAACT P1066
Stephen Spector*1, E Acosta2, N Zheng3, H Teppler4, B Homony4, E Handelsman5, C Worrell6, B Graham7, A Wiznia8, S Nachman9, and IMPAACT P1066 Study Team
1Univ of California, San Diego, La Jolla, US; 2Univ of Alabama at Birmingham, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Merck Res Labs, North Wales, PA, US; 5DAIDS, NIAID, NIH, Bethesda, MD, US; 6Natl Inst of Child Hlth and Human Devt, NIH, Bethesda, MD, US; 7Frontier Sci and Tech Res Fndn, Buffalo, NY, US; 8Jacobi Med Ctr, Bronx, NY, US; and 9State Univ of New York at Stony Brook, US
Background: Raltegravir (RAL) is an HIV-1 integrase inhibitor approved for use in adults. P1066 is an open-label study of RAL in treatment experienced HIV+ youth; acceptable pharmacokinetics, safety, and short-term efficacy have been described in 6- to 18-year-olds receiving the adult formulation and 2- to 11-year-olds receiving a chewable tablet formulation. We report intensive pharmacokinetics, available safety data, and 12-week efficacy from cohort IV, 6-month- to <2-year-old subjects receiving the RAL oral granule formulation.
Methods: We enrolled 9 HIV+ 6 month-old to <2-year-old patients in a dose-finding study. Entry criteria included HIV RNA >1000 copies/mL, and either prior ARV experience or failure of PMTCT. Patients received weight-based RAL oral granule suspension at ~6 mg/kg, every 12 hours. Intensive pharmacokinetic samples were drawn between day 5 and 12, then ARV were optimized, when possible. Summary pharmacokinetic parameters were evaluated and a dose was selected for continued study using an area-under-the-curve (AUC12 hr) targeted design (geometric mean [GM] target range of 14 to 25 µM*h) with C12h target to exceed the RAL IC95 (31 nM). Virologic success was defined as HIV RNA <400 copies/mL or ≥1 log drop from baseline.
Results: Of the 9 patients (8 with pharmacokinetic data): 67% were male; 78% black; mean (SD) age, 13 months (6.3); log10 RNA, 5.68 copies/mL (0.95); CD4%, 21% (9%); CD4 count, 1338 cells (822); weight, 8.3 kg (2.6), dose, 5.94 mg/kg (0.42). Cohort GM values: AUC12hr, 20 µM*h; Cmax, 10.7 µM; and C12h, 115 nM. Of the 9 patients, 3 had 12 grade ≥3 adverse events, none related to study drug. Patient 1, 3 low ANC and 7 reports of elevated lipase with concurrent acute Epstein-Barr virus (EBV) infection; patient 2, dyspnea; and patient 3, low ANC. One child spit up (grade 1) after taking the study drug. No adverse events (to date) were reported after week 8, with no treatment discontinuation due to study drug. Virologic success was noted in 78% (95%CI 40% to 97%) of the 9 subjects at week 12. There was a median net gain in CD4% of 5 (–3 to 7) and CD4 cells of 687 (–297 to 1237) at week 12.
Conclusions: Using weight-based dosing of RAL oral granules at ~6 mg/kg every 12 hours, in 6 month- to 2-year-old patients, pharmacokinetic values achieved study targets and were similar to those observed in 2- to 11-year-old patients. The 6 mg/kg every 12 hours dose was chosen for continued study in this age group. These data suggest that RAL oral granules are safe and well tolerated by young children. Preliminary efficacy data through week 12 are favorable.