European Journal of Clinical Pharmacology

, Volume 68, Issue 4, pp 355–362

Placebo-controlled study of the effects of fingolimod on cardiac rate and rhythm and pulmonary function in healthy volunteers

Authors

    • Novartis Institutes of Biomedical Research
  • Sam Hariry
    • Novartis Pharma AG
  • Olivier J. David
    • Novartis Pharma AG
Pharmacodynamics

DOI: 10.1007/s00228-011-1146-9

Cite this article as:
Schmouder, R., Hariry, S. & David, O.J. Eur J Clin Pharmacol (2012) 68: 355. doi:10.1007/s00228-011-1146-9

Abstract

Purpose

Fingolimod (FTY720) is a sphingosine-1 phosphate-receptor (S1PR) modulator recently approved as a once-daily oral therapy for relapsing multiple sclerosis (MS) in many countries. As S1PRs are widely expressed, including in heart and lung tissues, this study investigated the possible effects of fingolimod on heart-rate circadian rhythm and pulmonary function.

Methods

Healthy volunteers (n = 39) were randomized to receive fingolimod 0.5 mg, 1.25 mg, or placebo for 14 days. Heart rate and measures of cardiac and pulmonary function were assessed during the study.

Results

Mean heart rate for the first 12 h postdose was lower for both fingolimod than for placebo groups (p < 0.001) and remained 10–15 bpm lower than placebo until day 14 (p < 0.05). Heart rate circadian rhythm, cardiac output, stroke volume, and systemic vascular resistance were similar among treatment groups throughout the study. There was no evidence of an effect of fingolimod on pulmonary function. Absolute lymphocyte counts decreased by approximately 70% from baseline in both fingolimod groups (day 14) and began to increase within 14 days of stopping treatment.

Conclusions

In healthy volunteers treated for 14 days, once-daily fingolimod doses of 0.5 mg and 1.25 mg had no effect on cardiac or pulmonary function beyond a transient decrease in heart rate at treatment initiation.

Keywords

Fingolimodheart ratepulmonary functioncardiac functionabsolute lymphocyte count

Introduction

Fingolimod (FTY720) is a sphingosine-1 phosphate-receptor (S1PR) modulator recently approved as a once-daily oral therapy for relapsing multiple sclerosis (MS) in many countries [17]. Fingolimod targets MS via effects on the immune system, and evidence from animal models indicates that it may also have actions in the central nervous system (CNS) [1, 2]. Fingolimod demonstrated promising activity in a placebo-controlled phase II study in which once-daily fingolimod capsules significantly reduced annualized relapse rate (ARR) and inflammatory activity on magnetic resonance imaging (MRI) scans at 6 months compared with placebo [3]. These results have been confirmed in two phase III studies; a 2-year, placebo-controlled study [FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis (FREEDOMS)] [7], and a 1-year study comparing fingolimod with intramuscular interferon beta-1a (IFNβ-1a) administered once weekly [TRial Assessing injectable interferoN vS FTY720 Oral in RrMS (TRANSFORMS)] [5]. The 2-year results from FREEDOMS show that fingolimod 0.5 mg significantly reduced ARR, risk of disability progression, inflammatory brain lesion activity, tissue damage, and brain atrophy compared with placebo [7]. In TRANSFORMS, fingolimod 0.5 mg significantly reduced ARR by 52% compared with IFNβ-1a at 1 year; moreover, reductions in inflammatory brain lesion activity and rate of brain atrophy were superior with fingolimod [5].

Fingolimod exerts its therapeutic effects by modulating S1PRs, which are expressed in a wide variety of cell types, including lymphocytes and cells in the CNS, including glia and neurons [1, 2]. S1PRs modulation on lymphocytes by fingolimod retains circulating lymphocytes in the lymph nodes, thereby reducing recirculation of autoreactive lymphocytes and preventing their infiltration into the CNS [1, 2]. This is beneficial in MS because infiltration of autoreactive lymphocytes into the CNS leads to inflammation, tissue damage, and ultimately brain atrophy [8]. S1PRs are also expressed on cardiac and pulmonary tissues [911]. As a result, fingolimod therapy may affect heart and lung function, as has been observed in the phase II and III studies in patients with relapsing–remitting MS. The phase II study investigated fingolimod doses of 1.25 mg and 5.0 mg and reported that treatment initiation was associated with a transient decrease in heart rate [3], an effect that has also been reported in healthy volunteers [1214]. Transient effects on heart rate were also reported in the FREEDOMS and TRANSFORMS phase III studies, which investigated fingolimod doses of 0.5 mg and 1.25 mg and monitored heart rate following administration of the first dose of fingolimod. In the phase II and III studies, investigations into pulmonary function revealed minor changes in the forced expiratory volume in 1 s (FEV1) after 1 month of fingolimod treatment that remained stable thereafter [3, 5, 7]. Here we report the findings of a randomized, placebo-controlled, phase I study in healthy volunteers to further inform clinical practice with regard to the pharmacodynamic effects of the 0.5 mg and 1.25 mg doses of fingolimod on heart rate and lung function. In particular, we report the effects of fingolimod on mean and low outlier heart rate, circadian rhythm of heart rate; hemodynamic variables; normal lung function, bronchial hyperreactivity, and β-adrenergic-receptor-mediated small-airway dilation. In addition, given the effects of fingolimod on the immune system, absolute lymphocyte counts (ALC) were monitored throughout the 14 days of dosing and for a further 28 days after treatment cessation.

Methods

Participants

This single-center, randomized, double-blind, placebo-controlled, parallel-group, multiple-dose study was conducted between November 2006 and March 2007 in the USA. All volunteers provided written informed consent before participating. The study was conducted in compliance with the ethical principles of the Declaration of Helsinki and the study and any amendments were reviewed by the Institutional Review Board for the center. Healthy, nonsmoking men and women were eligible for study inclusion if they were aged 19–50 years, had a resting heart rate of 50–100 bpm, a systolic blood pressure of 90–140 mmHg, a diastolic blood pressure of 45–90 mmHg, and a body mass index (BMI) of 18–30 kg/m2. Key exclusion criteria included the use of any prescription drug within 4 weeks before dosing or over-the-counter medications within 2 weeks before dosing; absolute lymphocyte count (ALC) < 0.6 × 109 cells/L at screening; history of abnormal electrocardiograms (ECGs); bronchospastic disease or cardiovascular disease; or significant illness (judged by the investigator) within 2 weeks before dosing.

Study design and objectives

Participants received placebo on day −day 1 and were then randomized equally on day 1 to receive once-daily fingolimod 0.5 mg or 1.25 mg capsules, or matching placebo capsules for 2 weeks (days 1–14). Participants were admitted to a study center from day −2 to day 3, after which they were discharged as outpatients and returned to the study center for follow-up visits on days 7, 8, 14, 15, 28, and 42. When at the study center, study medication was administered between 08:00 and 10:00 h with 240 ml of water on each dosing day within 5 min of consumption of a standard breakfast. On days when the volunteers self-administered medication as outpatients, doses were taken at the same time and participants were free to assume their usual daily activities immediately after dosing.

The primary objective of the study was to measure the effect of fingolimod therapy initiation on heart rate. This was assessed by comparing the average heart rate [i.e., area under the time–effect curve across the 24-h postdose period (AUEC0–24) divided by 24] on day 1 between the fingolimod treatment and placebo groups. Secondary objectives included measuring the effect of treatment on heart rhythm; duration of dynamic effects on heart rate and rhythm; effects of treatment initiation on cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR) and duration of these effects; effects of treatment initiation on pulmonary function and duration of this effect; and pharmacodynamic effects on ALC.

Assessment of cardiac function and haemodynamics

Minimum, average, and maximum hourly heart rates were derived using 24-h, three-lead, digital Holter monitoring on days −1, 1, 7, and 14. Change in AUEC0–24 and minimum values over the 24-h postdose period were derived separately on days 1, 7, and 14 from the hourly average heart-rate data. Cardiac function was evaluated on days −1, 1, 7, 14, and 28 using M-mode, two-dimensional ECG imaging to assess CO, SV, and SVR.

Assessment of pulmonary function

Pulmonary function was assessed using spirometry on days −1, 1, 2, 7, 14, and 28. FEV1, forced vital capacity (FVC), forced midexpiratory flow rate (FEF25–75%), and FEV1/FVC were determined at each time point, and the effect on FEV1 of ascending doses of inhaled methacholine (0.025–25 mg) and albuterol 0.083 μg were assessed on days −1, 1, 2, 7, 14, and 28. The methacholine challenge was used to assess bronchial hyperreactivity, and albuterol was used to assess β-adrenergic-receptor-mediated small-airway dilation in the setting of fingolimod treatment. Oxygen saturation of arterial blood was measured by pulse oximetry performed at rest and during exercise challenge on days −1, 1, 2, 7, 14, and 28.

Other assessments

ALC data were obtained over 12 h after dosing on days −1 and 1 and in the morning of days 2, 3, 7, 8, 14, 15, 28, and 42. AUEC in the 12-h postdose (AUEC0–12) and nadir ALC values were derived for days −1 and 1. Safety assessments, including a physical examination, measurement of vital signs, standard clinical laboratory evaluations (blood chemistry, urinalysis, and hematology), and adverse event (AE) monitoring were also performed at specified time points.

Statistical methods

To assess the effect of fingolimod therapy initiation on heart rate, the 24-h heart rate recorded on day −1 (when all participants received placebo) was compared with the 24-h heart rate on day 1 for participants who receiving orally administered fingolimod treatment. The change in heart-rate AUEC0–24 between day −1 and day 1 was the primary endpoint of the study. Based on data from a previous placebo-controlled, pharmacodynamic study of fingolimod in healthy volunteers [13], the standard deviation (SD) for absolute change in heart-rate AUEC0–24 between days −1 and 1 was assumed to be 50 bpm × h for both fingolimod 1.25 mg and placebo. A sample size of 12 volunteers per group was thus required to provide 80% power to detect a difference of 60 bpm × h (i.e.. 5 bpm over 12 h) using Student’s t test with a two-sided type I error rate of 5% for comparison between fingolimod and placebo groups. No sample size adjustment for dropout was made because a replacement procedure was implemented in this study. The effect of fingolimod on the heart-rate AUEC0–24 on day 1 was assessed by fitting a linear model to data that included treatment as a factor and heart-rate AUEC0–24 on day −1 as the covariate. The effect of treatment over time and the day-by-dose interaction were assessed using a longitudinal mixed-effect model, with the day as a repeated effect. Descriptive statistics were calculated for all other pharmacodynamic endpoints. Mean and 95% confidence intervals (CI) were determined for cardiac function test data (CO, SV, and SVR), ALC data, and all pulmonary function test data, except FEV1, for which mean and SD were determined. The pharmacodynamic population consisted of randomized participants with evaluable pharmacodynamic measurements who received at least one dose of study drug, and the safety population consisted of all participants who received at least one dose of study drug with at least one postbaseline safety assessment.

Results

Study population and disposition

We randomized 39 volunteers to treatment (fingolimod 0.5 mg, n = 12; fingolimod 1.25 mg, n = 13; placebo, n = 14). One participant in the placebo group was withdrawn from the study without receiving medication because of inadequate baseline pulmonary function tests. Of the 38 participants who received treatment and were included in the pharmacodynamic analysis population, one (fingolimod 1.25 mg group) discontinued due to an AE (nonsustained ventricular tachycardia on day −1 and day 1) and one (placebo) completed all assessments but was withdrawn from study drug on day 7 because of a suspected viral infection. Baseline demographics were similar among treatment groups (see Table 1).
Table 1

Participant disposition and baseline demographics

  

Fingolimod 0.5 mg

Fingolimod 1.25 mg

Placebo

Participants

Randomized (n)

12

13

14

 

Exposed (n)

12

13

13

 

Completed (n)

12

12

13a

Age

Mean ± SD (years)

36.6 ± 9.0

34.8 ± 9.6

37.1 ± 10.6

Gender

Male (%)

6 (50.0)

6 (46.2)

8 (61.5)

Ethnicity

Caucasian (%)

11 (91.7)

9 (69.2)

9 (69.2)

 

Black (%)

1 (7.7)

2 (15.4)

 

Asian (%)

1 (8.3)

 

Hispanic (%)

3 (23.1)

2 (15.4)

Weight

Mean ± SD (kg)

75.1 ± 13.2

72.2 ± 9.1

78.6 ± 14.2

SD standard deviation

aOne participant from the placebo group completed study assessments and is included in the analyses but was withdrawn from study drug on day 7

Heart rate and cardiac function

Averaged hourly heart rates for days −1, 1, 7, and 14 are shown in Fig. 1. On day −1 (following administration of placebo), heart-rate profiles for all three treatment groups were similar, with mean heart rate (i.e., AUEC0–12 divided by 12) ranging from 80 to 83 bpm in the 12 h after receiving placebo (Fig. 1a). On day 1, there was a dose-dependent reduction in adjusted mean heart rate in both fingolimod groups in the first 12 h after dosing [fingolimod 0.5 mg 73.6 bpm, adjusted mean treatment difference 7.9 bpm (95% CI 4.6–11.3); fingolimod 1.25 mg, 69.6 bpm, adjusted mean treatment difference 11.9 bpm (95% CI 8.7–15.1)] compared with the placebo group (81.5 bpm; p < 0.001 for both comparisons) (Fig. 1b). In the fingolimod 0.5-mg group, a decrease in heart rate became evident approximately 5 h postdose and persisted for approximately 8 h, after which heart rate was similar to that in the placebo group. In the fingolimod 1.25 mg group, the decrease in heart rate became evident approximately 3 h postdose and persisted for the remainder of the 24-h dosing interval. The adjusted mean nadir heart rates during hours 0–12 were significantly lower in both fingolimod treatment groups [fingolimod 0.5 mg, 65.4 bpm, adjusted mean treatment difference 6.2 bpm (95% CI 2.4, 10.1); 1.25 mg, 60.8 bpm, adjusted mean treatment difference 10.8 bpm (95% CI 7.2–14.3) than in the placebo group (71.6 bpm; p < 0.01 and 0.001, respectively)]. Low, outlier, hourly heart rates, defined as 1.5 times lower than the interquartile range were measured for the three treatment groups on day 1. Using this definition, the lowest outlier hourly heart rate during the first 6 h after treatment initiation was approximately 58 bpm in the fingolimod 0.5 mg group and 48 bpm in the 1.25 mg group (42 bpm at 7 h post first dose) compared with approximately 60 bpm in the placebo group.
https://static-content.springer.com/image/art%3A10.1007%2Fs00228-011-1146-9/MediaObjects/228_2011_1146_Fig1_HTML.gif
Fig. 1

Effect of fingolimod on average heart rate on a day −1 (placebo run-in), b day 1 (treatment initiation), c day 7, and d day 14 (last day of treatment). Data are expressed as average hourly heart rate (AUEC0–24 divided by 24) in beats per minute (bpm) ± 95% confidence intervals. AUEC0–24, area under the time–effect curve across the 24-h postdose period

On day 7, mean heart rates for both fingolimod groups remained significantly lower (by approximately 10–15 bpm) than placebo throughout the 24-h dosing interval (p < 0.0001 for the 12 h postdose) (Fig. 1c). By day 14, the heart rates over 12 h postdose for both fingolimod groups were still approximately 10 bpm below that of placebo (p < 0.05 for both comparisons) and not significantly different from day 1 (p > 0.25 for both comparisons) (Fig. 1d).

Throughout the study, heart rate circadian rhythm was similar across the fingolimod and placebo groups (Fig. 1a–d). There were no significant changes during the study from baseline in the hemodynamic variables CO, SV, and SVR in any treatment group (Fig. 2). Maximum CO decrease was 12.0% (p = 0.26; Fig. 2a) and SV 10.7% (p = 0.17; Fig. 2b), both occurring in the placebo group on day 1. The maximum decrease in SVR was 10.3% in the fingolimod 1.25 mg group on day 7 (p = 0.5; Fig. 2c).
https://static-content.springer.com/image/art%3A10.1007%2Fs00228-011-1146-9/MediaObjects/228_2011_1146_Fig2_HTML.gif
Fig. 2

Effect of fingolimod treatment on cardiac function: a cardiac output; b stroke volume; c systemic vascular resistance. Data expressed as mean ± 95% confidence intervals

Pulmonary function

Neither fingolimod dose appeared to have an effect on airway resistance, as evident from measurements of FEV1, FVC, FEF25–75%, and FEV1/FVC. For all four parameters, values were comparable for day −1 (i.e., after receiving placebo) and day 1, and the 95% CIs for mean FEV1, FVC, FEF25–75%, and FEV1/FVC overlapped for both fingolimod groups and the placebo group at all time points (Fig. 3).
https://static-content.springer.com/image/art%3A10.1007%2Fs00228-011-1146-9/MediaObjects/228_2011_1146_Fig3_HTML.gif
Fig. 3

Effect of fingolimod treatment on pulmonary function: a forced expiratory volume in the first-second (FEV1); b forced expiratory vital capacity (FVC); c forced midexpiratory flow rate (FEF25–75%); d FEV1/FVC

Following a methacholine challenge, a dose-dependent decrease in FEV1 was observed on day 1 with methacholine doses of 0.25–25 mg in all treatment groups (data not shown). The dose response to challenge with methacholine was similar in all three treatment groups, indicating that neither fingolimod dose increased bronchial hyperreactivity. No consistent bronchodilatory response to inhaled albuterol 0.083 μg was observed on day −1 in any treatment group. The effect of albuterol challenge during treatment was similar among groups, indicating that fingolimod therapy did not elicit a paradoxical increase in airway resistance to albuterol challenge. Treatment with fingolimod had no effect on mean oxygen saturation at rest or during exercise challenge at any point during the study (data not shown).

Absolute lymphocyte counts

During the entire course of the study, the mean placebo group ALC remained relatively constant at about 1.5 x 109 cells/L. Following fingolimod administration on day 1, mean ALC decreased rapidly in a dose-dependent manner, decreasing by 0.412 x 109 cells/L (95% CI 0.275–0.548) in the fingolimod 0.5 mg group and by 0.693 x 109 cells/L (95% CI 0.562–0.824) in the fingolimod 1.25 mg group during the 12 h postdose (Fig. 4). In addition, both fingolimod treatment groups exhibited a significant decrease in ALC AUEC0–12 compared with placebo on day 1 (p ≤ 0.0004). After 14 days of treatment, mean ALCs for both fingolimod groups were 0.5 x 109 cells/L. After fingolimod treatment cessation, ALC began to increase, with a mean above the lower limit of normal (defined as 0.8 x 109 cells/L) for both groups after 14 days (study day 28) and were similar to placebo levels by 28 days (study day 42) (Fig. 4).
https://static-content.springer.com/image/art%3A10.1007%2Fs00228-011-1146-9/MediaObjects/228_2011_1146_Fig4_HTML.gif
Fig. 4

Effect of fingolimod treatment on absolute lymphocyte counts over the entire study period

Safety and tolerability

AEs were reported in 30 of 38 participants during the study. All AEs were mild to moderate in severity, and their incidence was roughly equal across the three treatment groups (placebo n = 9; fingolimod 0.5 mg, n = 11; fingolimod 1.25 mg, n = 10). One patient in the fingolimod 1.25 mg group was withdrawn from the study because of nonsustained ventricular tachycardia on day −1 and day 1 and left the study after dosing on day 3. AEs reported in three or more patients in any treatment group are shown in Table 2. Headache was the most frequently reported AE, occurring in a similar number of participants among treatment groups, and was considered to be related to treatment in five volunteers (placebo, n = 2; fingolimod 0.5 mg, n = 1; fingolimod 1.25 mg, n = 2). Based on adverse events detected by Holter monitoring, three participants, all in the 1.25-mg treatment group, experienced a heart rate < 50 bpm, which resolved without intervention. Compared with the placebo group and the day −1 values, there was no increase in the Holter-monitor-measured incidence of heart rhythm abnormalities in either of fingolimod treatment group. There was one report of palpitations in the fingolimod 1.25-mg group that resolved without treatment. No serious AEs or deaths were reported in any treatment group.
Table 2

Adverse events (AEs) reported in three or more patients in any treatment group

 

Placebo

Fingolimod

Fingolimod

N = 13

0.5 mg

1.25 mg

n (%)

N = 12

N = 13

n (%)

n (%)

Total numbers of participants with AEs

9 (69.2)

11 (91.7)

10 (76.9%)

Headache

4 (30.8)

6 (50.0)

3 (23.1)

Pharyngolaryngeal pain

5 (38.5)

3 (25.0)

0 (0.0)

Sinus congestion

3 (23.1)

2 (16.7)

1 (7.7)

Lymph node palpable

3 (23.1)

1 (8.3)

1 (7.7)

Cough

3 (23.1)

1 (8.3)

0 (0.0)

Pain in extremity

3 (23.1)

0 (0.0)

0 (0.0)

Discussion

The results of this study indicate that at daily doses of 0.5 and 1.25 mg – dosages that have demonstrated significant therapeutic benefits in the phase III FREEDOMS and TRANSFORMS studies in patients with relapsing–remitting MS – fingolimod did not affect heart rate circadian rhythm, ventricular function, vascular resistance, or pulmonary function during 14-day treatment in healthy volunteers. A dose-dependent decrease in heart rate was observed on treatment initiation, becoming apparent within 3–5 h of receiving the first dose of fingolimod. The decrease in heart rate after dosing with fingolimod was still evident after 14 days, but the magnitude of this effect did not increase with repeated dosing. These data add to those obtained from phase II and phase III studies in MS patients that indicated that the negative chronotropic effect of fingolimod 0.5 mg and 1.25 mg was mild and transient and that the small number of symptomatic bradycardia events observed in these MS studies occurred only after the first dose of fingolimod [5, 7].

The observed dose-dependent reduction in heart rate of approximately 10–15 bpm following treatment initiation was consistent with previous studies [3, 5, 7, 1214] . The mechanism of homeostatic response of the heart to fingolimod is thought to be due to activation of an inwardly rectifying Gαi-protein-regulated potassium channel (GIRK/IKACh), expressed on atrial myocytes and endothelial cells, resulting in decreased heart rate [13]. Repeated administration of fingolimod results in internalization of the S1PRs and cessation of signaling [13]. This assertion is supported by the observation that no incremental decrease in heart rate occurred after day 1 with additional once-daily doses of fingolimod, despite increasing blood concentrations, and no clinically notable effects on heart rate were evident with continued dosing in the phase III FREEDOMS and TRANSFORMS studies [5, 7]. Given that S1PRs are expressed on alveolar epithelium and capillary endothelium in the lung and are involved in the regulation of airway smooth-muscle tone and hypertrophy and the control of the alveolar–capillary barrier [10], it may be expected that S1PRs modulation by fingolimod would affect pulmonary function. However, in our study, no significant effects on FEV1, FVC, FEF25–75, or FEV1/FVC were detected in participants initiating fingolimod treatment 0.5 mg or 1.25 mg. These results are consistent with those of the phase II and TRANSFORMS phase III studies in which reductions in FEV1 in patients with relapsing MS treated with fingolimod 0.5 mg or 1.25 mg were limited to 2–3%, with no further reductions thereafter [3, 5]. Larger reductions from baseline in FEV1 of 8.8%, compared with 1.9% for placebo, were reported at 6 months in patients in the fingolimod 5.0-mg group in the phase II study; these reductions were generally transient and limited to the first few weeks of treatment [3]. Furthermore, during the extension phase of this study, pulmonary function remained stable, although dyspnea or asthma were reported more frequently in the fingolimod 5.0-mg group than in the 1.25-mg group [4]. These data suggest that pulmonary effects of fingolimod are mild and of minimal clinical impact at the doses used in the MS clinical program and recently approved for relapsing MS in some countries.

A rapid reduction in ALC to approximately 70% of pretreatment levels by day 14 was observed in our study for both fingolimod doses and is consistent with previous findings in healthy volunteers [12, 14]. Similar decreases in ALC were also observed in the phase II and III studies in patients with MS, occurring within 1 month of initiating therapy and remaining stable thereafter [3, 5, 7]. Because fingolimod retains a subset of lymphocytes in lymph nodes, a reduction in peripheral lymphocyte counts is an expected pharmacodynamic effect and accounts, at least in part, for the efficacy of fingolimod in MS. Importantly, reduction in peripheral blood lymphocyte count by fingolimod reflects retention of subsets of lymphocytes in the lymph nodes, not lymphocyte depletion, thereby accounting for a rapid recovery in lymphocyte count following treatment discontinuation [15, 16]. Unlike classic immunosuppressants, fingolimod does not affect activation, expansion, or proliferation of T or B lymphocytes [17]. The capacity for the lymphocyte count to recover is supported by the observation that the reduction in ALC in our study began to reverse toward baseline levels as soon as treatment was withdrawn. This reversal ran parallel to the decrease in fingolimod blood levels upon discontinuation of active treatment.

An important limitation of this study is that, whereas the number of participants was adequate to evaluate the pharmacodynamic effects of fingolimod on heart rate, pulmonary function, and peripheral lymphocyte counts, it is unlikely to be sufficient to reliably detect AEs with a frequency <10%. It is also important to note that our study was conducted in healthy volunteers and therefore provides little guidance on the possible effects of fingolimod in patients with existing cardiovascular disease. Furthermore, treatment duration was 2 weeks, which gives an insight into the dynamic effects of fingolimod during initiation of therapy but is not long enough to measure dynamic effects at steady state, which typically occurs after approximately 4–6 weeks of daily dosing. However, data from the ongoing phase II and III trials in MS patients provides evidence that there was no significant effect on heart rate with continued dosing, nor was there any worsening of pulmonary function with continued dosing [5, 7]. Furthermore, with continuous therapy, peripheral lymphocyte count remains at a mean level similar to that measured in our study.

In summary, heart rate circadian rhythm, ventricular function, airway resistance, oxygen exchange, and airflow were unaffected in healthy volunteers over a 14-day period following initiation of fingolimod therapy at doses investigated in phase III studies. The effect of fingolimod on heart rate did not increase in magnitude with continued treatment but did not recover to pretreatment levels within the short timescale of this study. These results add to those of phase II and III studies in MS patients that indicate that heart rate does return to toward baseline values with continued treatment and that symptomatic bradycardia is rare, transient, and self-limiting. This clinical pharmacology study, therefore, provides further elucidation of the safety profile of fingolimod, as demonstrated in clinical trials in MS to date.

Acknowledgments

The authors take full responsibility for the content of the paper but thank Sarah Griffiths, Rowena Hughes, and Eric Southam (Oxford PharmaGenesis™ Ltd) for editorial assistance, collating the comments of authors and other named contributors, and editing the paper for submission. The authors are grateful for the technical contributions of Thomas Dumortier.

Conflict of interest disclosure

This study was supported by Novartis Pharmaceuticals Corporation, New Jersey, USA.

Copyright information

© Springer-Verlag 2011