Initial PK, safety and 12 week efficacy of raltegravir chewable tablets in children 6-11 years

Polly Clayden, HIV i-Base

The raltegravir paediatric programme is ongoing in collaboration with IMPAACT (P1006). Children and adolescents age 2-18 who have failed at least one previous regimen, with viral load >1000 copies/mL are eligible. Age strata are accrued sequentially with the oldest group first.

Acceptable pharmacokinetics (PK), safety and short term efficacy has been reported for 6-11 and 12-18 year olds receiving the adult formulation. (poster 873)

In an oral presentation, Sharon Nachman presented initial PK, 12-week efficacy and safety data (as of January 4 2010) for children age 6-11 receiving a new chewable raltegravir tablet.

In this study, raltegravir was added to the children’s existing antiretroviral regimen. Intensive PK sampling was performed between days 5-12 and then background therapy was optimised.

This was an AUC targeted design for the chewable formulation based on adult data. PK parameters and variability were compared to the adult formulation in children of the same age range.

There were 10 children in this cohort, of which 50% were male, 60% white and 30% black. They were a median of 8.5 years old and 33 kg in weight. Their median absolute CD4, CD4% and viral load were 456 cells/mm3, 22.5% and 4.2 log respectively. The median follow up was 19 weeks.

Initially the dose studied was 8 mg/kg (n = 4). This was reduced to 6 mg/kg because of the high AUC12 with maximum dose of 300 mg.  All dosing was twice daily.

The actual geometric mean (GM) chewable formulation dose was 223 mg (vs 400 mg adult formulation).

At 6 mg/kg, GM AUC12 was 22.6 (range 12.8- 40.6) Mxh (n = 10). GM raltegravir trough (C12h) and peak (Cmax) concentrations were 128 (range 62-397) nM and 10.5 (4-23) uM, respectively.

Raltegravir oral clearance (CL/F) was 21 L/hr for chewable vs 49.6 L/hr for adult formulations. Overall PK variability (%CV) was less for chewable vs adult formulations (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 grade 4 events and no treatment discontinuations. At Week 12, 7/10 children (70%, 95%CI 35% to 93%) had viral load <400 copies/mL (3/7 initially received 8 mg/kg).

The investigators concluded that the raltegravir chewable tablet had less PK variability and lower oral clearance compared to the adult tablet. The differences in clearance are likely to be due to greater relative bioavailability of the chewable tablet.

Study of raltegravir in children age 6-11 will continue with a dose of 6mg/kg (maximum 300mg) of the chewable tablet.

Ref: Nachman S et al. Interim results from IMPAACT P1066: raltegravir oral chewable tablet formulation in children 6 to 11 Years. 17th CROI, 16-19 February 2010, San Francisco. Oral abstract 161LB.

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