Journal article
Pharmacometric model of agalsidase-migalastat interaction in human: a novel mechanistic model of drug-drug interaction between a therapeutic protein and a small molecule
Journal of pharmacokinetics and pharmacodynamics, Vol.50(1), pp.63-74
2023
DOI: 10.1007/s10928-022-09830-y
PMID: 36376611
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 k(on), dissociated with first order dissociation constant k(off), 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.
Details
- Title: Subtitle
- Pharmacometric model of agalsidase-migalastat interaction in human: a novel mechanistic model of drug-drug interaction between a therapeutic protein and a small molecule
- Creators
- Thanh Bach - University of IowaNan Wu - University of IowaGuohua An - Univ Iowa, Coll Pharm, Div Pharmaceut & Translat Therapeut, Iowa City, IA 52242 USA
- Resource Type
- Journal article
- Publication Details
- Journal of pharmacokinetics and pharmacodynamics, Vol.50(1), pp.63-74
- Publisher
- Springer Nature
- DOI
- 10.1007/s10928-022-09830-y
- PMID
- 36376611
- ISSN
- 1567-567X
- eISSN
- 1573-8744
- Number of pages
- 12
- Grant note
- name: no funding has been received
- Language
- English
- Electronic publication date
- 11/14/2022
- Date published
- 2023
- Academic Unit
- Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984365891602771
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