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A Pharmacokinetic Comparison of Adult and Pediatric Formulations of Raltegravir (RAL) in Healthy Adults
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Reported by Jules Levin
CROI 2010 Feb 16-19 SF
DM Brainard,1 IN Gendrano III,1 B Jin,1 WW Lewis,2 LA Wenning,1 JA Wagner,1 M Iwamoto1
1Merck & Co., Inc., Whitehouse Station, NJ; 2Covance Clinical Research Unit, Dallas, TX
AUTHOR CONCLUSIONS
SSingle doses of 400 mg RAL POL formulation, EC formulation (administered in the fed and fasted states), and OG in a liquid suspension were generally well tolerated.
After single dose administration of RAL, the geometric mean C12hr values were similar for all three formulations whereas the geometric means for AUC0-∝ and Cmax of both the EC and OG formulations were moderately higher than that of the RAL POL formulation.
BBoth EC and OG formulations demonstrated lower variability (% CV) with respect to AUC0-∝ and Cmax as compared to the POL formulation.
Administration of RAL EC formulation with a high-fat meal slows the rate of absorption, without a clinically meaningful change in the extent of absorption.
ABSTRACT
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) C12hr 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 AUC0-∝ and Cmax, respectively, compared to POL. EC demonstrated a 1.8-fold and 3.2-fold higher AUC0-∝ and Cmax, respectively, compared to POL. Both EC and OG formulations had earlier median Tmax 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 high-fat meal led to an increase in C12hr [GMR (90% CI) for fed/fasted = 2.88 (2.21 , 3.75)], a decrease in Cmax [GMR (90% CI) = 0.38 (0.28 , 0.52)], a delay in Tmax [ median 0.5 hr in the fasted state and 1.0 hr in the fed state], and a similar AUC0-∝ [GMR (90% CI) = 0.94 (0.78 , 1.14)].
Conclusions: Overall, the C12hr was similar for all three formulations. Both pediatric formulations demonstrated moderately higher AUC0-∝ and Cmax 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.
BACKGROUND
RAL is a novel HIV-1 integrase strand transfer inhibitor indicated for the treatment of HIV-1 infection in adults.
HIV-1 infection is not limited to adults, thus pediatric development of this compound is underway.
Two pediatric formulations have been developed:
- Chewable ethylcellulose tablet (EC) formulation.
- Oral granules (OG) formulation for suspension.
A clinical study was conducted to:
- Assess the safety and tolerability of these pediatric formulations following single dose administration.
- Compare the plasma pharmacokinetic profiles of the pediatric formulations after single doses of 400 mg to that obtained after a single dose of the marketed poloxamer (POL) tablet formulation.
- Assess the effect of a high-fat meal on the pharmacokinetics of the EC formulation.
RESULTS
Back-transformed least squares mean and confidence interval from mixed effects model performed on the natural log-transformed values.
Median values presented for Tmax.
Harmonic mean (jack-knife standard deviation) values presented for t1/2I and t1/2T. For t1/2I, the N's for POL, EC, OG, and EC FED are 11, 12, 12, and 10, respectively.
SUMMARY OF PHARMACOKINETICS
CThe geometric mean 12hr of both 400 mg RAL OG and EC formulations were similar to that obtained with the RAL POL formulation.
TThe geometric mean AUC0-∝ of both 400 mg RAL OG and EC formulations were moderately higher (2.6- and 1.8-fold, respectively) than that obtained with the RAL POL formulation.
BBoth the EC and OG formulations had earlier median Tmax values compared with the POL (0.5 and 1.0 hours for the EC and OG formulations, respectively, compared to 4.0 hours for the POL).
Compared to administration of the EC formulation fasting, administration with a high-fat · meal led to an increase in C12hr, a decrease in Cmax, a delay in Tmax, and a similar AUC0-∝. Intersubject variability for C12hr was increased in the presence of food.
SAFETY
SSingle dose administration of each of the 400 mg RAL formulations was generally well tolerated in healthy adult male and female subjects.
NNo serious clinical or laboratory adverse experiences were reported; no subject discontinued because of an adverse experience.
SSix (6) subjects reported a total of 9 different nonserious clinical adverse experiences, 1 of which (somnolence) was judged by the investigator to be possibly related to study drug.
AAll adverse experiences reported were transient and rated as mild in intensity.
There were no laboratory adverse experiences reported in this study
Reference
1 Merschman, SA, Vallano PT, Wenning, LA, Matuszewski BK, Woolf EJ. Determination of the HIV integrase inhibitor, MK-0518 (raltegravir), in human plasma using 96-well liquid–liquid extraction and HPLC-MS/MS. J Chromatog B 2007; 857: 15-19.
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