Application of a physiologically based pharmacokinetic model for the evaluation of single-point plasma phenotyping method of CYP2D6

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Abstract

Purpose:

Determining metabolic ratio from single-point plasma is potentially a good phenotyping method of CYP2D6 to reduce the required time interval and increase the reliability of data. It is difficult to conduct large sample size clinical trials to evaluate this phenotyping method for multiple plasma points. A physiologically based pharmacokinetic (PBPK) model can be developed to do simulations based on the large virtual Chinese population and evaluate single-point plasma phenotyping method of CYP2D6.

Methods:

Pharmacokinetic data of dextromethorphan (DM) and its metabolite dextrorphan (DX) after oral administration were used for model development. The SimCYP® model incorporating Chinese demographic, physiological, and enzyme data was used to simulate DM and DX pharmacokinetics in different phenotype groups.

Results:

The ratios of the simulated to the observed mean AUC and Cmax of DM were 1.01 and 0.81 for extensive metabolizers (EMs), 0.90 and 0.81 for intermediate metabolizers (IMs), and 1.12 and 0.84 for poor metabolizers (PMs). The ratios of the simulated to the observed mean AUC and Cmax of DX were 1.12 and 0.89 for EMs, 0.66 and 0.62 for IMs. All ratios were within the predefined criterion of 0.5–2. The simulations of DM and DX pharmacokinetic profiles in 1000 virtual Chinese subjects with reported frequencies of different phenotypes indicated that statistically significant correlations were found between metabolic ratio of DM to DX (MRDM/DX) from AUC and from single-point plasma from 1 to 30 h (all p-values < 0.001).

Conclusion:

MRDM/DX from single-point plasma from 1 to 30 h after the administration of 30 mg controlled-release DM could predict the MRDM/DX from AUC well and could be used as the phenotyping method of CYP2D6 for EMs, IMs, and PMs.

Graphical abstract

In the present study, a dynamic PBPK model was developed for DM and its active metabolite DX in three CYP2D6 phenotype groups (EM, IM, and PM). A virtual Chinese population consisting of EM, IM, and PM subjects with the reported frequencies was developed to simulate the pharmacokinetic profiles of DM and DX in a large Chinese population. Statistically significant correlations were found between MRDM/DX from AUC0-inf and MRDM/DX from single-point plasma from 1 to 30 h (all p-values < 0.001). The simulation overcame some limitations of small clinical trials and indicated that MR from single-point plasma from 1 to 30 h after the administration of 30 mg CR DM could predict the MR from AUC well and could be used as the phenotyping method of CYP2D6 for EM, IM, and PM subjects.

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