Population pharmacokinetic analysis of rebamipide in healthy Korean subjects with the characterization of atypical complex absorption kinetics

In this study, the population pharmacokinetic (PK) analysis of rebamipide (Reba) in healthy male Korean subjects was analyzed using the nonlinear mixed effects modeling method. The possible effects of physiological covariates and the multidrug resistance (MDR1) gene 3435C > T polymorphism on PK parameters were also investigated. Data were collected from a bioequivalence study, in which 26 subjects who participated in the study were administered a single oral dose of 100 mg Reba; only data from the reference formulation were used. Reba showed a relatively large inter-individual variability (from 2.6- to 3.3-fold) in the PK parameters with double peaks or the concentration plateau after the peak concentration in its serum concentration-time profiles. The population PKs of Reba was best described by a one-compartment model with three fraction absorption processes followed a single Weibull-type function and two first-order kinetics, and lag times. The study suggests that the efflux transporter MDR1 3435C > T allele affects the substantial inter-individual variability in the absorption of Reba according to genetic polymorphism. A significant difference was found in the absorption rate ka (1) among the MDR1 3435C > T genotype groups (P < 0.05) (CT group, 79.8% increase; and TT group, 115% increase). The use of combined MDR1 3435C > T and body mass index as covariates for ka (1) exerted a more significant effect (P < 0.05). In addition, body surface area significantly affected the apparent total clearance (P < 0.05).