c Comparison of Adult and Pediatric Formulations of Raltegravir (RAL) in Healthy Adults

Background: RAL is a HIV-1 integrase strand transfer inhibitor approved for treatment of HIV-1 in combination with other antiretrovirals in adults. Infection is not limited to adults, thus pediatric development of this compound is warranted and underway. Two pediatric formulations have been developed: the chewable ethylcellulose (EC) formulation and an oral granule (OG) formulation for suspension. The current study evaluated the safety and tolerability of these pediatric formulations and compared their plasma pharmacokinetic profiles after single doses of 400 mg to that obtained after a single dose of the marketed poloxamer (POL) tablet formulation. In addition, the effect of a high-fat meal on the pharmacokinetics of the EC formulation was assessed. Methods: Open label, 4-period, randomized, crossover study in 12 adults. Treatment A: 400 mg RAL POL x 1. Treatment B: 400 mg RAL EC x 1. Treatment C: 400 mg RAL OG in suspension x 1. Treatment D: 400 mg RAL EC x 1 following a high-fat meal. There was a 4 day washout between each period. Results: No serious adverse experiences (AEs) were reported and there were no discontinuations due to drug related clinical or laboratory AEs. The geometric mean (GM) C 12hr of 400-mg RAL OG, EC and POL formulations was similar with an estimated geometric mean ratio (GMR) for OG/POL of 1.09 with 90% CI of (0.84, 1.41), and for EC/POL of 0.90 (0.70, 1.18). OG demonstrated a 2.6-fold and 4.6-fold higher AUC 0-∝ and C max , respectively, compared to POL. EC demonstrated a 1.8-fold and 3.2-fold higher AUC 0-∝ and C max , respectively, compared to POL. Both EC and OG formulations had earlier median T max values compared to POL (0.5 and 1.0 hours for EC and OG, respectively, compared to 4.0 hours for POL). For EC, compared to administration in the fasted state, administration with a highfat meal led to an increase in C 12hr [GMR (90% CI) for fed/ fasted = 2.88 (2.21 , 3.75)], a decrease in C max [GMR (90% CI) = 0.38 (0.28 , 0.52)], a delay in T max [ median 0.5 hr in the fasted state and 1.0 hr in the fed state], and a similar AUC 0-∝ [GMR (90% CI) = 0.94 (0.78 , 1.14)]. Conclusions: Overall, the C 12hr was similar for all three formulations. Both pediatric formulations demonstrated moderately higher AUC 0-∝ and C max values as compared to the POL formulation. A high-fat meal slowed the rate of absorption from the EC formulation, with no statistically meaningful change in extent of absorption. These data support further clinical investigation of the OG and EC pediatric formulations.