Ethnic sensitivity study of fingolimod in white and Asian subjects

Jm, Kovarik; Slade, Alan; Voss, Brigitta; Schmidli, Heinz; Gj, Riviere; Picard, Franck; Y, Sugita; Kawai, Ryoji; Mee-Lee, Denis; Rl, Schmouder

doi:10.5414/cpp45098

Cited by 23 publications

(34 citation statements)

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“…Hence, the phosphorylation of fingolimod is reversible, in line with the approximately constant concentration ratio of fingolimod to fingolimod phosphate in blood during the elimination phase (Fig. 2, inset), observed also in a previous study (Kovarik et al, 2007b). The phosphorylation of fingolimod is catalyzed predominantly by sphingosine kinase type 2 with a smaller contribution by sphingosine kinase type 1 (Billich et al, 2003;Paugh et al, 2003).…”

Section: Discussionsupporting

confidence: 54%

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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

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: Discussionsupporting

confidence: 54%

“…Two metabolites of fingolimod other than its phosphate have been quantified in clinical studies (e.g., Kovarik et al, 2005Kovarik et al, , 2006Kovarik et al, , 2007b. However, a full description of the biotransformation of the compound has not been published.…”

Section: Introductionmentioning

confidence: 99%

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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“…In a similar study with the non-selective S1P receptor modulator fingolimod, a slight decrease in exposure in Japanese subjects compared to Caucasians was observed [19]. Studies to date indicate that ponesimod metabolism is not mediated by CYP enzymes (Actelion, data on file), but the responsible enzymes remain to be identified [12,20,21].…”

Section: Discussionmentioning

confidence: 99%

Effects of Ethnicity and Sex on the Pharmacokinetics and Pharmacodynamics of the Selective Sphingosine-1-Phosphate Receptor 1 Modulator Ponesimod: A Clinical Study in Japanese and Caucasian Subjects

et al. 2014

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The aim of this study was to evaluate the relative pharmacokinetic (PK) and pharmacodynamic (PD) properties of a single dose of ponesimod, an oral and selective sphingosine-1-phosphate receptor 1 (S1P₁) modulator, in Japanese and Caucasian healthy subjects and explore the effects of sex on PK. Subjects received a single 40-mg dose of ponesimod in a single-centre, open-label, parallel-group study design. Ten Japanese and 10 Caucasian healthy subjects (age: 22-45 years, 1:1 sex ratio) participated in the study and were matched for body weight (w10%). Ponesimod concentration in plasma was determined by liquid chromatography tandem mass spectrometry, and PK parameters were obtained by non-compartmental analysis. Total lymphocyte count served as PD marker. Adverse events (AEs), laboratory values, electrocardiography (12-lead ECG), and vital signs were assessed for safety and tolerability. Administration of ponesimod resulted in similar PK parameters between the two ethnic groups, with a 16% higher exposure [AUC_0-_∞ of 7,368 ng · h/ml (95% CI: 6,059-8,962) vs. 6,353 ng · h/ml (4,950-8,154)] and a 17% longer terminal elimination half-life [32.9 h (30.1-36.0) vs. 28.1 h (23.4-33.6)] in Japanese compared to Caucasian subjects. Exposure was slightly higher in female subjects [7,488 ng · h/ml (5,983-9,371)] than in male subjects [6,252 ng · h/ml (5,031-7,771)]. The maximum mean lymphocyte count decrease from baseline, observed 6 h after receiving the dose in both groups, was similar in Japanese subjects (61.8%) and Caucasians (62.5%). The maximum mean heart rate (ECG) reduction from baseline was similar, with a difference of 4.2 bpm between Caucasian and Japanese subjects, observed 2.5 h after receiving the dose in both ethnic groups. There were no clinically relevant changes in other safety variables. No serious AEs were reported during the study. This study showed that the PK and PD profile of ponesimod was similar in Japanese and Caucasian subjects. No unexpected safety findings were reported. No dose adjustment is deemed necessary for Japanese subjects compared to Caucasians. i 2014 S. Karger AG, Basel

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“…In vivo, fingolimod is phosphorylated by the enzyme sphingosine‐1‐kinase to form the biologically active metabolite, fingolimod phosphate (fingolimod‐P), which is dephosphorylated back to the inactive form, fingolimod, before further metabolism . The pharmacokinetic (PK) profiles of fingolimod and fingolimod‐P have been extensively investigated in healthy subjects, renal transplant recipients, and patients with multiple sclerosis (MS) and are identical across the populations . Fingolimod exhibits high oral bioavailability (>90%), and its absorption is unaffected by dietary intake .…”

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confidence: 99%

Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in Healthy Subjects

David

Behrje

Pal

et al. 2018

Clinical Pharm in Drug Dev

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This open‐label, single‐sequence study in healthy subjects investigated the effects of steady‐state carbamazepine on the pharmacokinetic (PK) profile of a single 2‐mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up‐titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady‐state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod Cmax was reduced by 18% and AUCinf by 40%, as was T1/2 (106 vs 163 hours). A similar trend was observed for fingolimod‐P. Models linking fingolimod‐P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution.

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Ethnic sensitivity study of fingolimod in white and Asian subjects

Cited by 23 publications

References 0 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

Effects of Ethnicity and Sex on the Pharmacokinetics and Pharmacodynamics of the Selective Sphingosine-1-Phosphate Receptor 1 Modulator Ponesimod: A Clinical Study in Japanese and Caucasian Subjects

Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in Healthy Subjects

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