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<p>Although epinastine has been actively used in clinical practice for treatment of allergic diseases, attempts to interpret and quantify pharmacokinetic (PK) diversity within population have been very limited. In particular, there have been no studies on population-pharmacokinetic (pop-PK) modeling of epinastine focusing on genetic factors. The primary objective of this study was to quantitatively interpret the PK variability of epinastine according to phenotypic polymorphisms of cytochrome P450 (CYP) 2D6 in Korean population and to construct a new pop-PK model considering such polymorphisms. The bioequivalence PKs, physiologic and biochemical parameter analyses, and CYP2D6 genotyping results performed in 26 healthy Korean males were used in this study. The pop-PKs of epinastine were described by the first-order oral absorption and distribution between central and peripheral compartments, and elimination from the central compartment as the basic model structure. The covariate reflection of physiologic and biochemical parameters was not valid. Conversely, CYP2D6 phenotypic polymorphisms were explored as valid covariates for clearance from the central compartment (CL<sub>c</sub>/F). Compared to extensive-metabolizers (EMs), the decreases in typical CL<sub>c</sub>/F values in intermediate-metabolizers (IMs) and poor-metabolizers (PMs) were estimated as 28.06% and 49.48%, respectively. As a result of pop-PK model simulation, the serum concentrations of epinastine at steady-state significantly increased from CYP2D6 EMs to IMs and PMs. The degree of increase was 1.97 (in PMs compared to EMs) and 1.39 (in IMs compared to EMs) based on the corresponding value of 50% of the group. This study provides a new perspective on the quantitative interpretation of PK changes for epinastine according to CYP2D6 genotypic factors and is expected to be an important bridgehead for improving clinical efficacy and safety through precision pharmacotherapy.</p>

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Population modeling of pharmacokinetic variability of epinastine, a histamine H1 receptor antagonist, according to cytochrome P450 2D6 phenotypic polymorphisms

  • 期刊论文

  • 发表日期：

    2025年5月29日

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  • Ji-Hun Jang,
  • Seung-Hyun Jeong

摘要

Although epinastine has been actively used in clinical practice for treatment of allergic diseases, attempts to interpret and quantify pharmacokinetic (PK) diversity within population have been very limited. In particular, there have been no studies on population-pharmacokinetic (pop-PK) modeling of epinastine focusing on genetic factors. The primary objective of this study was to quantitatively interpret the PK variability of epinastine according to phenotypic polymorphisms of cytochrome P450 (CYP) 2D6 in Korean population and to construct a new pop-PK model considering such polymorphisms. The bioequivalence PKs, physiologic and biochemical parameter analyses, and CYP2D6 genotyping results performed in 26 healthy Korean males were used in this study. The pop-PKs of epinastine were described by the first-order oral absorption and distribution between central and peripheral compartments, and elimination from the central compartment as the basic model structure. The covariate reflection of physiologic and biochemical parameters was not valid. Conversely, CYP2D6 phenotypic polymorphisms were explored as valid covariates for clearance from the central compartment (CLc/F). Compared to extensive-metabolizers (EMs), the decreases in typical CLc/F values in intermediate-metabolizers (IMs) and poor-metabolizers (PMs) were estimated as 28.06% and 49.48%, respectively. As a result of pop-PK model simulation, the serum concentrations of epinastine at steady-state significantly increased from CYP2D6 EMs to IMs and PMs. The degree of increase was 1.97 (in PMs compared to EMs) and 1.39 (in IMs compared to EMs) based on the corresponding value of 50% of the group. This study provides a new perspective on the quantitative interpretation of PK changes for epinastine according to CYP2D6 genotypic factors and is expected to be an important bridgehead for improving clinical efficacy and safety through precision pharmacotherapy.