Dataset Information

A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers.

ABSTRACT:

Aims

Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects.

Methods

Plasma concentration-time data of agomelatine and its metabolites were collected from a 4-period, cross-over bioequivalence study, in which 44 healthy subjects received 25 mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics.

Results

A semiphysiological pharmacokinetic model with parallel first-order absorption and a well-stirred liver compartment adequately described the data. The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve-based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: -50 to 200%). Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6-109.1-fold.

Conclusions

A semiphysiological pharmacokinetic model incorporating first-pass hepatic extraction was developed for agomelatine and its main metabolites. The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure.

SUBMITTER: Xie F

PROVIDER: S-EPMC6475681 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers.

Xie Feifan F Vermeulen An A Colin Pieter P Cheng Zeneng Z

British journal of clinical pharmacology 20190321 5

<h4>Aims</h4>Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects.<h4>Methods</h4>Plasma concentration-time data of agomelatine and its metabolites were collected fr ...[more]

PMID: 30761579

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Project description:OBJECTIVE:Olanzapine is an atypical antipsychotic drug commonly used for the treatment of schizophrenia. However, there are still many complications associated with the use of olanzapine, and researchers continually strive to improve the handling of data from regular therapeutic drug monitoring (TDM). The objective of this study is to optimise the individualised treatment of olanzapine by establishing a population pharmacokinetics (PopPK) model in Chinese patients with schizophrenia. METHODS:This study integrates an extensive collection of concentration data from healthy volunteers after a single dose and a less extensive collection of samples from patients undergoing TDM. A PopPK model was developed using non-linear mixed-effects modelling. Potential covariates, including the olanzapine manufacturer and patient gender and age, were assessed during model development. A total of 616 plasma concentration levels from 22 healthy male individuals in China and 458 concentration levels from 112 male and 122 female patients with schizophrenia undergoing TDM at 12 hospitals in China were included in the analysis. The concentration profile could be best described using a two-compartment model with first-order absorption and elimination. RESULTS:The absorption rate (Ka) of olanzapine ranged from 2.85 h-1 to 5.39 h-1 for the different formulations. The typical absorption time delay was 0.877 hour. Body weight had a considerable effect on the apparent volume of the centre compartment and showed a power relationship. CONCLUSIONS:A PopPK model of olanzapine in Chinese patients with schizophrenia was developed in this study. After determining the PK parameters of olanzapine, the results suggested that body weight exhibited a considerable impact effect on VC/F. The impact of subjects and formulations requires further study. The PopPK model established in this study is likely to provide some information for the individualised therapy of olanzapine. TRIAL REGISTRATION NUMBER:ChiCTR-TRC-10000934; Results.

Dataset Information

A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers.

Aims

Methods

Results

Conclusions

Publications

A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers.

Similar Datasets

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