A pharmacokinetic comparison of adult and pediatric formulations of raltegravir in healthy adults

Elizabeth G Rhee, Matthew L Rizk, Diana M Brainard, Isaias N Gendrano, III, Bo Jin, Larissa A Wenning, John A Wagner, Marian Iwamoto
2014 Antiviral Therapy  
Raltegravir is an HIV-1 integrase inhibitor approved for use in adults, children and infants ≥4 weeks of age. As alternatives to the original film-coated tablet, a chewable ethylcellulose (EC) tablet and oral granules for suspension (GFS) have been developed for use in children. The purpose of this study was to evaluate these formulations in adults prior to use in paediatric studies. Methods: This open-label, 4-period, randomized, crossover study investigated the safety, tolerability and
more » ... rability and pharmacokinetics of raltegravir paediatric formulations and the effect of a high-fat meal on EC tablet pharmacokinetics in healthy adults. In a balanced, crossover design (with a 4-day washout between treatments), 12 subjects received one 400 mg film-coated tablet (fasted), four 100 mg EC tablets (fasted), one 400 mg GFS dose (fasted) and four 100 mg EC tablets (after a high-fat meal). Results: AUC 0-∞ and C max were 2.6-fold and 4.6-fold higher for GFS and 1.8-fold and 3.2-fold higher for EC versus film-coated tablets. The geometric mean C 12h values for the GFS formulation (162 nM) and the EC tablet (134 nM) were similar to that of the film-coated tablet (149 nM). Administration with a high-fat meal increased C 12h , decreased C max and delayed T max for the EC tablet, but did not affect AUC 0-∞ . There were no serious adverse events (AEs) and no discontinuations due to drug-related clinical or laboratory AEs. Conclusions: Both paediatric formulations demonstrate moderately higher AUC 0-∞ and C max , and similar C 12h compared with the film-coated tablet. These data support the use of raltegravir GFS and EC formulations in paediatric studies. Raltegravir is an integrase strand-transfer inhibitor indicated for the treatment of HIV-1 infection in adults, children and infants ≥4 weeks of age [1] [2] [3] [4] [5] . For adults and children >12 years of age, the recommended dosage is one 400 mg film-coated tablet twice daily. To provide alternative formulations for younger children, a chewable ethylcellulose (EC) tablet and oral granules for suspension (GFS) were developed. The EC tablet is approved in the US and European Union for use in toddlers and children, 2-12 years of age, as 25 and 100 mg tablets dosed by weight [1]. The GFS formulation was developed for the youngest paediatric patients who are unable to chew a tablet and was recently approved in the US for use in children and infants at least 4 weeks of age [1] . Raltegravir is dosed without regard to food, as prior studies have demonstrated that administration of the raltegravir film-coated tablet with food does not result in a meaningful change in raltegravir pharmacokinetics, although pharmacokinetic variability is increased compared with administration in the fasting state [6] . In the current study, we evaluated the safety, tolerability and pharmacokinetic profile of the paediatric GFS and EC formulations in healthy adult subjects prior to use in paediatric studies. We also assessed the effect of a high-fat meal on the plasma pharmacokinetic profile of the raltegravir EC formulation.
doi:10.3851/imp2765 pmid:24608069 fatcat:ysl3cuyskzfyvf26ouxavkkjqy