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. 2023 Feb;50(1):63-74.
doi: 10.1007/s10928-022-09830-y. Epub 2022 Nov 14.

Pharmacometric model of agalsidase-migalastat interaction in human: a novel mechanistic model of drug-drug interaction between a therapeutic protein and a small molecule

Thanh Bach #  1 , Nan Wu #  1 , Guohua An  2
Affiliations

Pharmacometric model of agalsidase-migalastat interaction in human: a novel mechanistic model of drug-drug interaction between a therapeutic protein and a small molecule

Thanh Bach et al. J Pharmacokinet Pharmacodyn. 2023 Feb.

Abstract

Recently, a new mechanism of drug-drug interaction (DDI) was reported between agalsidase, a therapeutic protein, and migalastat, a small molecule, both of which are treatment options of Fabry disease. Migalastat is a pharmacological chaperone that stabilizes the native form of both endogenous and exogenous agalsidase. In Fabry patients co-administrated with agalsidase and migalastat, the increase in active agalsidase exposure is considered a pharmacokinetic effect of agalsidase infusion but a pharmacodynamic effect of migalastat administration, which makes this new DDI mechanism even more interesting. To quantitatively characterize the interaction between agalsidase and migalastat in human, a pharmacometric DDI model was developed using literature reported concentration-time data. The final model includes three components: a 1-compartment linear model component for migalastat; a 2-compartment linear model component for agalsidase; and a DDI component where the agalsidase-migalastat complex is formed via second order association constant kon, dissociated with first order dissociation constant koff, and distributed/eliminated with same rates as agalsidase alone, albeit the complex (i.e., bound agalsidase) has higher enzyme activity compared to free agalsidase. The final model adequately captured several key features of the unique interaction between agalsidase and migalastat, and successfully characterized the kinetics of migalastat as well as the kinetics and activities of agalsidase when both drugs were used alone or in combination following different doses. Most parameters were reasonably estimated with good precision. Because the model includes mechanistic basis of therapeutic protein and small molecule pharmacological chaperone interaction, it can potentially serve as a foundational work for DDIs with similar mechanism.

Keywords: Agalsidase–Migalastat interaction; DDI model; Fabry disease; Mechanistic model; Novel mechanistic DDI model; Pharmacometric modeling.

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