Population pharmacokinetics of epinastine, a histamine H1 receptor antagonist, in adults and children.
OBJECTIVE
Our objective was to develop a population pharmacokinetic (PPK) model for epinastine, a histamine H(1) receptor antagonist, in adults and children and to obtain pharmacokinetic information to support dosing recommendations in children.


METHODS
A total of 1510 plasma samples were collected from 62 healthy adult volunteers and 62 paediatric atopic dermatitis patients. The data were analysed using the NONMEM program according to a two-compartment model with first-order absorption. In addition, the final PPK model was evaluated by means of bootstrapping resampling.


RESULTS
The oral clearance (CL/F) was found to be associated with body weight, formulation and food status. The volume of distribution of the central compartment (V(1)/F) was related to body weight and food status. An absorption lag time was apparent in fed subjects. On the other hand, other covariates (formulation on V(1)/F, volume of distribution of the peripheral compartment (V(2)/F), first-order absorption rate constant (Ka) and absorption lag time (ALAG); food status on V(2)/F and Ka; body weight on V(2)/F) were not statistically significant. No effect of age on CL/F, V(1)/F or V(2)/F was found. The mean parameter estimates obtained with an additional 200 bootstrap replicates of data were within 90-117% of those obtained with the original data set. These results suggest that the pharmacokinetics of epinastine are similar in adults and in children, except for the effect of the difference of body weight. The result of the application of the PPK model to the clinical trial in paediatric patients, in which dosage was determined based on the body weight (from 14 kg to less than 24 kg; 10 mg dose, 24 kg or more; 20 mg dose), showed that the C(max) and AUC (25.6 +/- 6.9 ng ml(-1) and 246.8 +/- 68.2 ng h ml(-1)) were almost same levels with those of adults after administration of 20 mg (26.9 +/- 9.1 ng ml(-1) and 281.6 +/- 90.5 ng h ml(-1)).


CONCLUSIONS
A PPK model for epinastine was established and further evaluation by bootstrapping indicated that this model is stable. The model shows that, if dosage is adjusted based on the body weight, the epinastine exposure in paediatric patients is similar to that in adults.
Sarashina
A
A
Department of Drug Metabolism and Pharmacokinetics, Kawanishi Pharma Research Institute, Nippon Boehringer Ingelheim Co. Ltd., Kawanishi 666-0193, Japan.
Tatami
S
S
Yamamura
N
N
Tsuda
Y
Y
Igarashi
T
T
D000328:Adult; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D003984:Dibenzazepines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007223:Infant; D008297:Male; D013997:Time Factors
D003984:Dibenzazepines; D006634:Histamine H1 Antagonists; D007093:Imidazoles; C053090:epinastine