Oral‐intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects

Kovarik, John M.; Hartmann, Stefan; Bartlett, Mark; Riviere, Gilles-Jacques; Neddermann, Daniel; Wang, Yibin; Port, Andreas; Schmouder, Robert

doi:10.1002/bdd.535

Cited by 48 publications

(55 citation statements)

References 10 publications

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“…The extent of absorption was estimated to be Ն84% of dose, based on the amount of radioactivity excreted in urine (81% of dose) (Table 4) and the amount of metabolites excreted in feces (Ն3% of dose) ( Table 3). The absolute bioavailability (F) could not be determined in the present study but can be assumed to be high (Kovarik et al, 2007a). The low apparent clearance of fingolimod (CL/F, 8.7 Ϯ 3.7 l/h), its high apparent terminal volume of distribution (V z /F, 1509 Ϯ 225 liters), and its long terminal half-life (137 Ϯ 55 h) (Table 1) are in line with data from previous studies (Kovarik et al, 2004(Kovarik et al, , 2006.…”

Section: Discussionmentioning

confidence: 88%

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

Zollinger¹,

Gschwind²,

Jin³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Fingolimod [(FTY720), Gilenya; 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol], a new drug for the treatment of relapsing multiple sclerosis, acts through its phosphate metabolite, which modulates sphingosine 1-phosphate receptors. This represents a novel mechanism of action. In the present work, the absorption and disposition of 14 C-labeled fingolimod were investigated in healthy male volunteers after a single oral dose of 4.5 mg. Total radioactivity was determined in blood, urine, and feces. Fingolimod was quantified in blood. Metabolite profiles were determined in blood and excreta, and metabolite structures were elucidated by mass spectrometry, wet-chemical methods, and comparison with reference compounds. Fingolimod was absorbed slowly but almost completely. The biotransformation of fingolimod involved three main pathways: 1) reversible phosphorylation to fingolimod phosphate [(S)-enantiomer, active principle]; 2) -hydroxylation at the octyl chain, catalyzed predominantly by CYP4F enzymes, followed by further oxidation to a carboxylic acid and subsequent ␤-oxidation; and 3) formation of ceramide analogs by conjugation with endogenous fatty acids. This metabolism is quite unusual because it follows metabolic pathways of structurally related endogenous compounds rather than biotransformations typical for xenobiotics. The elimination of fingolimod was slow and occurred predominantly by oxidative metabolism whereas fingolimod phosphate was eliminated mainly by dephosphorylation back to fingolimod. Drug-related material was excreted mostly in the urine in the form of oxidation products.

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Section: Discussionmentioning

confidence: 88%

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

Zollinger¹,

Gschwind²,

Jin³

et al. 2010

Drug Metab Dispos

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“…These case reports did not report on blood pressure or stated it was stable. Neutropenia and lymphopenia are associated with therapeutic fingolimod administration and may be observed within days of the first dose [6]. The most Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Our patient had both neutropenia and lymphopenia at presentation, which stabilised after during her admission, with a neutrophil count of 1. Fingolimod is efficiently absorbed with an oral bioavailability of >90 %, and absorption is unaffected by meals with dose-proportional exposure between 0.125 and 5 mg in single and multi-dose studies [6]. Blood drug concentrations rise slowly to reach broad plateau 8 to 36 h post-administration with absolute c max reaching generally 12-16 h post-dose and may occur over a long length of the gastrointestinal tract [7].…”

Section: Discussionmentioning

confidence: 99%

Deliberate Fingolimod Overdose Presenting with Delayed Hypotension and Bradycardia Responsive to Atropine

et al. 2013

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Introduction Fingolimod is an immunomodulating agent used in multiple sclerosis (MS). It is a sphingosine-1-phosphate (S1P) receptor agonist prescribed for relapsing forms of MS to delay onset of physical disability. As fingolimod is known to cause first-dose bradycardia, telemetry is recommended for the first 6 h post-dose. We present the first reported case of deliberate fingolimod overdose requiring atropine administration for bradycardia and hemodynamic instability. Case report A 33-year-old woman ingested 14 mg of fingolimod and 2 g of phenoxymethylpenicillin. After presenting to the emergency department 19 h later, she was initially hemodynamically stable (heart rate (HR) 60, blood pressure (BP) 113/89 mmHg). Two hours later, she then developed bradycardia (HR 48) and hypotension (87/57 mmHg). Despite intravenous fluids, stabilisation was only achieved after administration of atropine (300 μg). She was then admitted to the intensive care unit (ICU) for further monitoring where another episode of bradycardia and hypotension required atropine. She was monitored in the ICU for 48 h and then discharged on day 5 with no further episodes.Discussion Fingolimod is known to cause bradycardia in the first 6 h post first therapeutic dose. Following intentional overdose, onset of bradycardia occurred at 21 h postingestion and was associated with hypotension. Atropine was successful in treating bradycardia and associated hypotension.

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“…Fingolimod is phosphorylated peripherally (Olivera et al, 1998;Liu et al, 2000), in the platelets in blood (Albert et al, 2005) and presystemically during first pass in the liver upon oral administration (Kovarik et al, 2007). 2.…”

Section: Methodsmentioning

confidence: 99%

“…Fingolimod is an interesting model compound to investigate the pharmacokinetics of S1PHK substrates, because the interconversion between fingolimod and its phosphate has been well investigated in several in vitro, in vivo, and ex vivo studies (Olivera et al, 1998;Liu et al, 2000;Billich et al, 2003;Albert et al, 2005;Kovarik et al, 2007;Kihara and Igarashi, 2008). From ex vivo studies it is known that fingolimod is phosphorylated in the blood platelets (Albert et al, 2005;Anada et al, 2007;Kihara and Igarashi, 2008).…”

Section: Introductionmentioning

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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Oral‐intravenous crossover study of fingolimod pharmacokinetics, lymphocyte responses and cardiac effects

Cited by 48 publications

References 10 publications

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

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

Deliberate Fingolimod Overdose Presenting with Delayed Hypotension and Bradycardia Responsive to Atropine

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

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