Migalastat Tissue Distribution: Extrapolation From Mice to Humans Using Pharmacokinetic Modeling and Comparison With Agalsidase Beta Tissue Distribution in Mice.

Abstract

Approved therapies for Fabry disease (FD) include migalastat, an oral pharmacological chaperone, and agalsidase beta and agalsidase alfa, 2 forms of enzyme replacement therapy. Broad tissue distribution may be beneficial for clinical efficacy in FD, which has severe manifestations in multiple organs. Here, migalastat and agalsidase beta biodistribution were assessed in mice and modeled using physiologically based pharmacokinetic (PBPK) analysis, and migalastat biodistribution was subsequently extrapolated to humans. In mice, migalastat concentration was highest in kidneys and the small intestine, 2 FD-relevant organs. Agalsidase beta was predominantly sequestered in the liver and spleen (organs unaffected in FD). PBPK modeling predicted that migalastat 123 mg every other day resulted in concentrations exceeding the in vitro half-maximal effective concentration in kidneys, small intestine, skin, heart, and liver in human subjects. However, extrapolation of mouse agalsidase beta concentrations to humans was unsuccessful. In conclusion, migalastat may distribute to tissues that are inaccessible to intravenous agalsidase beta in mice, and extrapolation of mouse migalastat concentrations to humans showed adequate tissue penetration, particularly in FD-relevant organs.

• Authors: Yi Shuan Wu, Richie Khanna, Virginia Schmith, Yi Lun, Jin-Song Shen, Anadina Garcia, Leo Dungan, Anthony Perry, Lukas Martin, Pai-Chi Tsai, Rick Hamler, Anibh M Das, Raphael Schiffmann, Franklin K Johnson
• Journal: Clinical pharmacology in drug development (Clin Pharmacol Drug Dev) Vol. 10 Issue 9 Pg. 1075-1088 (09 2021) ISSN: 2160-7648 [Electronic] United States
• PMID: 33876577 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 Amicus Therapeutics Inc. Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Chemical References

• Isoenzymes
• 1-Deoxynojirimycin
• migalastat
• alpha-Galactosidase
• agalsidase beta

Topics

• 1-Deoxynojirimycin (analogs & derivatives, pharmacokinetics)
• Adult
• Animals
• Female
• Humans
• Isoenzymes (pharmacokinetics)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Middle Aged
• Models, Biological
• Species Specificity
• Tissue Distribution
• Young Adult
• alpha-Galactosidase (genetics, pharmacokinetics)