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.

CYP1A2 polymorphism may contribute to agomelatine-induced acute liver injury

“…Due to the extensive hepatic first-pass extraction of AGM following oral administration, the concentrations of the metabolites are much higher than those of the parent drug AGM . [ 30 ] In particular, our patient with the rs762551 AA genotype exhibited a significantly lower level of AGM exposure compared to the rs762551 CC genotype. Therefore, liver injury with elevated liver enzymes may not be caused by the high blood concentration of AGM itself.…”

Agomelatine's antiglycoxidative action—In vitro and in silico research and systematic literature review

“…None of the four main metabolites of agomelatine (7-desmethyl agomelatine, 3-hydroxyagomelatine, dihydrodiol-agomelatine, and desacetamide-agomelatine-carboxylic acid) exerts antidepressant effects; however, at least one may prevent protein glycation/oxidation. This is most likely to be the case with 7-desmethyl agomelatine, which passes through the blood–brain barrier to a high degree, as does the parent compound ( 91 , 92 ). Therefore, further studies on evaluating the antiglycoxidative properties of agomelatine metabolites are needed.…”