Paper # 161LB|
Interim Results from IMPAACT P1066: Raltegravir Oral Chewable Tablet Formulation in Children 6 to 11 Years
Sharon Nachman*1, E Acosta2, P Samson3, H Teppler4, B Homony4, T Fenton3, E Handelsman5, C Worrell6, B Graham7, A Wiznia8, and the 1066 Group
1State Univ of New York at Stony Brook, US; 2Univ of Alabama at Birmingham, US; 3Harvard Sch of Publ Hlth, Boston, MA, US; 4Merck Res Labs, North Wales, PA, US; 5Div of AIDS, 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; and 8Jacobi Med Ctr, Bronx, NY, US
Background: áRaltegravir (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 were seen in 6 to 11 and 12 to 18 year-olds
(Cohorts IIA and I) receiving the adult formulation (AF). Here, we report initial
pharmacokinetics, 12-week efficacy, and all safety data as of 1 Dec 2009 from
Cohort IIB, 6 to 11 year-old subjects receiving a new oral chewable tablet (OCT)
formulation of RAL.
Methods: áHIV+ youth enrolled in Stage 1:
dose-finding with intensive pharmacokinetics, safety and week 12 virologic
response. Entry criteria included HIV RNA>1000 copies/mL, being treatment
experienced but na´ve to integrase inhibitors, and excluded subjects with HBV
or HCV. RAL was added to existing ARV regimen, intensive pharmacokinetics
sampling occurred between days 5 and 12, then ARV were optimized. Pharmacokinetics
was summarized for OCT and a dose was selected for continued study using an
area-under-the-curve (AUC) targeted design based on adult pharmacokinetics
data. Pharmacokinetics parameters and variability were compared to the AF in
children ages 6 to 11 years (Cohort IIA).
Results: Baseline demographics: N = 10. 50%
Male; Race: 60% White, 30% Black; Median: weight = 33 kg; age = 8.5year;
log10RNA = 4.2; CD4 = 456 cells/uL. Median
follow-up = 19 weeks. The initial dose studied was 8 mg/kg (n = 4);
due to high AUC12 this was lowered to 6 mg/kg with maximum of
300 mg; all dosing was twice daily. The actual geometric mean (GM) OCT dose was
223 mg (vs 400 mg AF in Cohort IIA). At 6 mg/kg, GM (range) AUC12
was 22.6 (12.8 to 40.6) mMxh (n = 10).
GM RAL trough (C12h) and peak (Cmax) concentrations were 128 (62 to
397) nM and 10.5 (4 to 23) mM,
respectively. RAL oral clearance (CL/F) was 21 L/hr for OCT vs 49.6 L/hr for
AF. Overall pharmacokinetics variability (%CV) was less for OCT vs AF (AUC12,
34 vs 120%; Cmax, 53 vs 130%; C12h, 84 vs 221%). There
was one grade 3 adverse event: possibly related (elevated fasting LDL). There
were no treatment discontinuations. At Week 12, 7/10 subjects (70%, 95%CI 35%
to 93%) had RNA <400 copies/mL (3 of the 7 first received 8 mg/kg).
Conclusions: The RAL chewable tablet had less pharmacokinetics
variability and lower oral clearance, as compared to the adult tablet.
Differences in clearance are likely due to greater relative bioavailability of
the chewable tablet. A RAL dose of 6 mg/kg (maximum 300 mg) twice daily of
the chewable tablet was chosen for continued study in HIV+ youth
ages 6 to 11. In these subjects, RAL appeared to be generally safe and well-tolerated.
Week 12 efficacy data were favorable.