Translational Pharmacokinetic Modeling of Fingolimod (FTY720) as a Paradigm Compound Subject to Sphingosine Kinase-Mediated Phosphorylation

• Published in: Drug metabolism and disposition Vol. 42; no. 9; pp. 1367 - 1378
• Main Authors: Snelder, Nelleke, Ploeger, Bart A., Luttringer, Olivier, Stanski, Donald. R., Danhof, Meindert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2014
• Subjects: Administration, Intravenous; Administration, Oral; Animals; Blood Platelets - metabolism; Double-Blind Method; Fingolimod Hydrochloride; Humans; Lysophospholipids - metabolism; Male; Phosphates - metabolism; Phosphorylation - drug effects; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Propylene Glycols - administration & dosage; Propylene Glycols - pharmacokinetics; Randomized Controlled Trials as Topic; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Sphingosine - administration & dosage; Sphingosine - analogs & derivatives; Sphingosine - metabolism; Sphingosine - pharmacokinetics; Km; S1P; Vin vivo; fingolimod-P; ka; Vm; PBPK; Kd; PK; S1PHK; LOQ
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.113.056770

A complicating factor in the translational pharmacology of sphingosine 1-phosphate agonists is that they exert their pharmacological effect through their respective phosphate metabolites, which are formed by the enzyme sphingosine kinase (S1PHK). In this investigation, we present a semimechanistic pharmacokinetic model for the interconversion of S1PHK substrates and their respective phosphates in rats and humans with the aim of investigating whether characterization of the rate of phosphorylation in blood platelets constitutes a basis for interspecies scaling using fingolimod as a model compound. Data on the time course of fingolimod and fingolimod-phosphate (fingolimod-P) blood concentrations after intravenous and oral administration of fingolimod and/or fingolimod-P in rats and after oral administration of fingolimod in doses of 0.5, 1.25, and 5 mg once daily in healthy volunteers were analyzed in conjunction with data on the ex vivo interconversion and blood-plasma distribution in rat and human blood, respectively. Integrating the data from the ex vivo and in vivo studies enabled simulation of fingolimod and fingolimod-P concentrations in plasma rather than blood, which are more relevant for characterizing drug effects. Large interspecies differences in the rate of phosphorylation between rats and humans were quantified. In human, phosphorylation of fingolimod in the platelets was four times slower compared with rat, whereas the dephosphorylation rates were comparable in both species. This partly explained the 10–12-fold overprediction of fingolimod-P exposure in human when applying a dose-by-factor approach on the developed rat model. Additionally, differences in presystemic phosphorylation should also be taken into account.