No dose adjustment of metformin or substrates of organic cation transporters (OCT)1 and OCT2 and multidrug and toxin extrusion protein (MATE)1/2K with fostemsavir coadministration based on modeling approaches.

Autor: Nguyen D; GlaxoSmithKline, Collegeville, Pennsylvania, USA., Miao X; GlaxoSmithKline, Collegeville, Pennsylvania, USA., Taskar K; GlaxoSmithKline, Ware, UK., Magee M; GlaxoSmithKline, Collegeville, Pennsylvania, USA., Gorycki P; GlaxoSmithKline, Collegeville, Pennsylvania, USA., Moore K; Allucent, Cary, North Carolina, USA., Tai G; GlaxoSmithKline, Collegeville, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: Pharmacology research & perspectives [Pharmacol Res Perspect] 2024 Aug; Vol. 12 (4), pp. e1238.
DOI: 10.1002/prp2.1238
Abstrakt: Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.
(© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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