TY  - JOUR
T1  - Quantitative Evaluation of How OATP1B1 and OATP2B1 Genetic Polymorphisms Influence Fexofenadine Pharmacokinetic Variability Using Pharmacometrics
A1  - Isabelle Dubois
A1  - Louis Martin
A1  - Sophie Lefevre
JF  - Annals of Pharmacy Practice and Pharmacotherapy
JO  - Ann Pharm Pract Pharmacother
SN  - 3062-4436
Y1  - 2021
VL  - 1
IS  - 1
DO  - 10.51847/buKVfS67GP
SP  - 101
EP  - 117
N2  - Fexofenadine is widely employed for treating various allergic conditions, yet limited data exist regarding its pharmacokinetic variability and the quantitative determinants influencing it. This study sought to validate previously suggested genetic factors using population pharmacokinetic modeling of fexofenadine and to quantify the genetic contributions affecting its pharmacokinetic diversity. Polymorphisms in the organic-anion-transporting-polypeptides (OATP) 1B1 and 2B1 have been implicated in interindividual differences in fexofenadine disposition; thus, pharmacokinetic modeling was conducted based on oral exposure data stratified by these polymorphisms. The analysis identified OATP1B1 and OATP2B1 as significant covariates influencing apparent clearance (CL/F) and the relationship between volume of distribution (V/F) and CL/F, respectively. Depending on the OATP1B1 genotype, fexofenadine CL/F and average steady-state plasma concentrations varied by as much as 2.17- and 2.20-fold, respectively. Similarly, subjects with different OATP2B1 variants exhibited up to 1.73- and 2.00-fold differences in CL/F and V/F. The ratios of the area under the curve (AUC) after single and multiple doses, along with cumulative AUC ratios, significantly differed across OATP1B1 and OATP2B1 genotype groups. Quantitative modeling outcomes demonstrated that OATP1B1 exerts a stronger influence on fexofenadine pharmacokinetic variability than OATP2B1. Furthermore, based on the established pharmacokinetic–pharmacodynamic model, fexofenadine efficacy varied by approximately 1.25- and 0.87-fold according to OATP1B1 and OATP2B1 polymorphisms, respectively, indicating that OATP1B1 genetic variability may also play a meaningful role in pharmacodynamic responses. Collectively, this population pharmacometric investigation provides a valuable framework for advancing precision medicine approaches to optimize fexofenadine therapy.
UR  - https://galaxypub.co/article/quantitative-evaluation-of-how-oatp1b1-and-oatp2b1-genetic-polymorphisms-influence-fexofenadine-phar-ixm2gzssqwhtnze
ER  -