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Population Pharmacokinetics of Fingolimod Phosphate in Healthy Participants
Author(s) -
Wu Kai,
Mercier Francois,
David Olivier J.,
Schmouder Robert L.,
Looby Michael
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011409229
Subject(s) - fingolimod , pharmacokinetics , pharmacology , medicine , population , bioavailability , multiple sclerosis , immunology , environmental health
Fingolimod (FTY720) is a sphingosine 1‐phosphate receptor (S1PR) modulator currently being evaluated for the treatment of multiple sclerosis. Fingolimod undergoes phosphorylation in vivo to yield fingolimod phosphate (fingolimod‐P), which modulates S1PRs expressed on lymphocytes and cells in the central nervous system. The authors developed a population model, using pooled data from 7 phase 1 studies, to enable characterization of fingolimod‐P pharmacokinetics following oral administration of fingolimod and to evaluate the impact of key demographic variables on exposure. The fingolimod‐P concentration‐time course after either single or multiple doses of fingolimod was described by a 2‐compartment model with first‐order apparent formation and elimination, lag time in the apparent formation, and dose‐dependent relative bioavailability and apparent central volume of distribution. Body weight and ethnicity were identified as demographic covariates correlated with the disposition of fingolimod‐P. Model predictions indicated no need for dose adjustment of fingolimod based on body weight; the effect of ethnicity on the disposition of fingolimod requires further investigation. The accurate prediction of the pharmacokinetic profile of fingolimod‐P determined empirically in 2 large phase 3 trials provides external validation of the model.