The utility of mixed‐effects covariate analysis in rapid selection of doses in pediatric subjects: A case study with fexofenadine hydrochloride

Abstract

Fexofenadine hydrochloride is a non-sedating antihistamine that is used in the treatment of symptoms associated with seasonal allergic rhinitis and chronic idiopathic urticaria. A pooled analysis of pharmacokinetic data from children 6 months to 12 years of age and adults was conducted to identify the dose(s) in children that produce exposures comparable to those in adults for the treatment of seasonal allergic rhinitis. The pharmacokinetic parameter database included peak and overall exposure data from 269 treatment exposures from 136 adult subjects, and 90 treatment exposures from 77 pediatric allergic rhinitis patients. The data were pooled and analysed using NONMEM software, version 5.0. A covariate model based on body weight and age and a power function model based on body weight were identified as appropriate models to describe the variability in fexofenadine oral clearance and peak concentration, respectively. Individual oral clearance estimates were on average 44%, 36% and 61% lower in children 6 to 12 years (n=14), 2 to 5 years (n=21), and 6 months to 2 years (n=42), respectively, compared with adults. Trial simulations (n=100) were carried out based on the final pharmacostatistical models and parameter estimates to identify the appropriate dose(s) in children relative to the marketed dose of 60 mg fexofenadine hydrochloride in adults. The trials were designed as crossover studies in 18 subjects comprising various potential dosing regimens with and without weight stratification. Pharmacokinetic parameter variability was assumed to have a log-normal distribution. Individual weights and ages were simulated using mean (SD) estimates derived from the studies used in this analysis and proportional measurement/model mis-specification errors derived from the analysis were incorporated into the simulation. The results indicated that a 30 mg dose of fexofenadine hydrochloride administered to children 1 to 12 years of age and weighing >10.5 kg and a 15 mg dose administered to children 6 months and older and weighing <or=10.5 kg produces exposures similar to those seen with the 60 mg dose in adults.

Fexofenadine in horses: pharmacokinetics, pharmacodynamics and effect of ivermectin pretreatment

“…The bioavailability of fexofenadine in man has not been determined in detail, but appears to be higher than in horse and mouse (Lippert et al. , 1995; Krishna et al. , 2004).…”

“…administration of fexofenadine in horse the C max in plasma was about 86 ng/mL after dosing at 10 mg/kg bw. This can be compared with man, in which the C max in serum was reported to be about 450 ng/mL after oral doses of about 3 mg/kg bw of fexofenadine (Krishna et al. , 2004).…”

An Overview of the Pediatric Medications for the Symptomatic Treatment of Allergic Rhinitis, Cough, and Cold

“…Fexofenadine was well tolerated, and no unexpected AEs were observed. Population analysis showed that the apparent oral clearance estimate of fexofenadine was 36% lower in pediatric subjects 2 to 5 years compared to adult subjects . As the clinical formulation in the PK and safety studies were not suited for marketing, an oral suspension formulation was developed later as the to‐be‐marketed formulation.…”

“…Population analysis showed that the apparent oral clearance estimate of fexofenadine was 36% lower in pediatric subjects 2 to 5 years compared to adult subjects. 21,71 As the clinical formulation in the PK and safety studies were not suited for marketing, an oral suspension formulation was developed later as the to-be-marketed formulation. The formulation bridging program comprised of three PK studies to evaluate the bioavailability, bioequivalence and food effect of the suspension formulation.…”

Population approaches in paediatrics

“…Krishna et al. [12] showed also the utility of this approach in rapid selection of doses of fexofenadine in paediatric patients. As clinical development of drugs in adults usually precedes that in children, the PK data accumulated in adults should help the analysis of those from children.…”