FTY720: Placebo‐Controlled Study of the Effect on Cardiac Rate and Rhythm in Healthy Subjects

Abstract

895The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) FTY720 is a novel immunomodulator that acts as a sphingosine-1-phosphate (S1P) receptor agonist, thereby reducing the recirculation of lymphocytes to blood and peripheral tissues, including inflammatory lesions and graft sites. [1][2][3][4] In contrast to classic immunosuppressants, FTY720 does not impair cellular or humoral immunity to systemic viral infection and does not affect the activation, expansion, or proliferation of T lymphocytes or immunological memory in preclinical models. 5FTY720 was effective in prolonging allograft survival in preclinical models of cardiac, renal, and hepatic transplantation. 4 Furthermore, a synergistic effect was noted when FTY720 was used in combination with subtherapeutic or therapeutic doses of cyclosporine in a number of different allograft models. 4 The results of phase II clinical studies demonstrated that FTY720 can be used effectively and safely in combination with classic immunosuppressive agents, including cyclosporine 6 and everolimus. 7 FTY720 has been well tolerated in comparative studies conducted in renal transplant recipients to date. However, a recurring finding in these trials has been a reduction in heart rate with initiation of FTY720 treatment. [6][7][8][9] This negative chronotropic effect appears to be temporally associated with the first dose of FTY720. A nadir in heart rate is observed within 4 to 12 hours of drug administration, with heart rate recovering close to baseline within 48 hours after a single dose of FTY720.6-9 The mechanism underlying the effect of FTY720 on heart rate appears to be mediated by its capacity to agonize S1P

The lymphocyte migration inhibitor FTY720 attenuates experimental hypertensive nephropathy

“…First, FTY720 has been found to modulate blood pressure in general, an effect that depends on the relative distribution of S1P receptors in the endothelium and smooth muscle cell layer of the blood vessel exposed. Some studies have shown a small, transient decrease in mean arterial pressure in animals and humans (20,25), which is possibly explained by a similar modest and by a transient decrease in heart rate by FTY720 (25). In contrast, increases in mean arterial pressure by S1P Fig.…”

S1P Signaling and De Novo Biosynthesis in Blood Pressure Homeostasis

“…It is also possible that FTY720 could act on the kidneys, thus influencing BP, although 7-day FTY720 treatment at supratherapeutic doses did not alter renal functions and structure (Tawadrous et al, 2002). Corroborating these results, clinical studies assessing the therapeutic effects of FTY720 in healthy volunteers and multiple sclerosis patients reported transient bradycardia within 6 hours after the first dose of FTY720, and delay in atrioventricular conduction (Kappos et al, 2006Schmouder et al, 2006;Cohen et al, 2010;Calabresi et al, 2014;Gold et al, 2014). These acute effects were paralleled by a small and transient decrease in systolic and diastolic BP (Kovarik et al, 2008;DiMarco et al, 2014).…”

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

“…122 In clinical trials, fingolimod induced a transient, dose-dependent, usually mild negative chronotropic effect, reaching a maximum 4 to 5 hours after the first dose and attenuating over time despite continued dosing and increasing blood levels. 123 In a pooled analysis of FREE-DOMS and TRANSFORMS, there were mean reductions of $8bpm at nadir with the 0.5mg dose and $11bpm with 1.25mg. 124 The decrease in heart rate usually was asymptomatic; in the phase III trials, dizziness, fatigue, chest discomfort, and palpitations were reported in <1% of fingolimod-treated patients, and there were no cases of syncope.…”