Absorption and Disposition of the Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) in Healthy Volunteers: A Case of Xenobiotic Biotransformation Following Endogenous Metabolic Pathways

Zollinger, Markus; Gschwind, Hans‐Peter; Jin, Yi; Sayer, Claudia; Zécri, Frédéric; Hartmann, Stefan

doi:10.1124/dmd.110.035907

Cited by 40 publications

(38 citation statements)

References 27 publications

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“…The important role of the liver in the metabolism of fingolimod was shown in liver impaired patients: fingolimod AUC increased and its half-life was prolonged and exposure to fingolimod phosphate increased in a manner related to the severity of the liver function impairment [62]. Absorption and disposition of 14 C-labeled fingolimod were further investigated in healthy subjects [64] and revealed that fingolimod is mainly metabolized via three pathways and the major route of excretion is urine. Administration of fingolimod intravenously and orally allowed to estimate a high apparent absolute bioavailability of 93 % [65].…”

Section: Pharmacokinetics Of Fingolimodmentioning

confidence: 99%

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Juif

Kraehenbuehl

Dingemanse

2016

Expert Opinion on Drug Metabolism & Toxicology

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The safety profile of S1P receptor modulators is considered better than other classes of immunomodulators and was further improved by the development of up-titration regimens to mitigate first-dose effects. S1P receptor modulators display similar pharmacodynamic effects but have very different pharmacokinetic profiles. Drugs with a rapid elimination are of interest in case of opportunistic infections or pregnancy, whereas the need of re-initiation of up-titration in case of treatment interruption can present a challenge.

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Section: Pharmacokinetics Of Fingolimodmentioning

confidence: 99%

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Juif

Kraehenbuehl

Dingemanse

2016

Expert Opinion on Drug Metabolism & Toxicology

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“…In terms of metabolites, hydroxylation of both FTY720-C2 and FTY720-Mitoxy were identified early in 1 hr incubations (Figs 1 and 3). As previously mentioned in the Introduction to this paper, one of the biotransformation pathways of FTY720 is ω-hydroxylation at the octyl chain being the first step, followed by further oxidation and subsequent β-oxidation to yield different length carboxylic acid metabolites [41]. Human hepatocytes generated similar levels of hydroxy FTY720-C2 and FTY720-Mitoxy (Figs 1B and 3B), but in rat hepatocytes, hydroxy FTY720-C2 was produced in larger amounts than was hydroxy FTY720-Mitoxy (Figs 1A and 3A); again, suggesting species-specific differences.…”

Section: Discussionmentioning

confidence: 99%

“…The full absorption, distribution, metabolism, and excretion (ADME) data on FTY720 (fingolimod) are well described for humans [39–41]. FTY720 blood concentrations slowly reach maxima at ~ 12 to 24 hr after oral dosing and follow a slow decline with elimination half-life of about 7 days [42].…”

Section: Introductionmentioning

confidence: 99%

“…FTY720 blood concentrations slowly reach maxima at ~ 12 to 24 hr after oral dosing and follow a slow decline with elimination half-life of about 7 days [42]. FTY720 is highly metabolized in human, and three biotransformation pathways have been reported, that include the reversible formation of FTY720 phosphate by sphingosine kinase; acylations with endogenous fatty acids at the amino group of FTY720; ω-hydroxylation at the octyl chain by CYP4F to form the octyl-alcohol metabolite M12 (not observed in vivo), and further oxidation to a carboxylic acid metabolite M1 (octanoic acid metabolite), followed by subsequent β-oxidation to generate a series of carboxylic acids (M2-M4) that are excreted in the urine [40, 41]. …”

Section: Introductionmentioning

confidence: 99%

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Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

Enoru¹,

Yang

Krishnamachari

et al. 2016

PLoS ONE

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Parkinson’s disease (PD) is a neurodegenerative aging disorder in which postmortem PD brain exhibits neuroinflammation, as well as synucleinopathy-associated protein phosphatase 2A (PP2A) enzymatic activity loss. Based on our translational research, we began evaluating the PD-repurposing-potential of an anti-inflammatory, neuroprotective, and PP2A stimulatory oral drug that is FDA-approved for multiple sclerosis, FTY720 (fingolimod, Gilenya®). We also designed two new FTY720 analogues, FTY720-C2 and FTY720-Mitoxy, with modifications that affect drug potency and mitochondrial localization, respectively. Herein, we describe the metabolic stability and metabolic profiling of FTY720-C2 and FTY720-Mitoxy in liver microsomes and hepatocytes. Using mouse, rat, dog, monkey, and human liver microsomes the intrinsic clearance of FTY720-C2 was 22.5, 79.5, 6.0, 20.2 and 18.3 μL/min/mg; and for FTY720-Mitoxy was 1.8, 7.8, 1.4, 135.0 and 17.5 μL/min/mg, respectively. In hepatocytes, both FTY720-C2 and FTY720-Mitoxy were metabolized from the octyl side chain, generating a series of carboxylic acids similar to the parent FTY720, but without phosphorylated metabolites. To assess absorption and distribution, we gave equivalent single intravenous (IV) or oral doses of FTY720-C2 or FTY720-Mitoxy to C57BL/6 mice, with two mice per time point evaluated. After IV delivery, both FTY720-C2 and FTY720-Mitoxy were rapidly detected in plasma and brain; and reached peak concentrations at the first sampling time points. After oral dosing, FTY720-C2 was present in plasma and brain, although FTY720-Mitoxy was not orally bioavailable. Brain-to-plasma ratio of both compounds increased time-dependently, suggesting a preferential partitioning to the brain. PP2A activity in mouse adrenal gland increased ~2-fold after FTY720-C2 or FTY720-Mitoxy, as compared to untreated controls. In summary, FTY720-C2 and FTY720-Mitoxy both (i) crossed the blood-brain-barrier; (ii) produced metabolites similar to FTY720, except without phosphorylated species that cause S1P1-mediated-immunosuppression; and (iii) stimulated in vivo PP2A activity, all of which encourage additional preclinical assessment.

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“…2. Fingolimod-P is dephosphorylated back to fingolimod before it is eliminated from the body (Zollinger et al, 2011). 3.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2014

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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 bloodplasma 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 doseby-factor approach on the developed rat model. Additionally, differences in presystemic phosphorylation should also be taken into account.

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Absorption and Disposition of the Sphingosine 1-Phosphate Receptor Modulator Fingolimod (FTY720) in Healthy Volunteers: A Case of Xenobiotic Biotransformation Following Endogenous Metabolic Pathways

Cited by 40 publications

References 27 publications

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators

Preclinical Metabolism, Pharmacokinetics and In Vivo Analysis of New Blood-Brain-Barrier Penetrant Fingolimod Analogues: FTY720-C2 and FTY720-Mitoxy

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

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