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

ABSTRACT

Introduction: Sphingosine-1-phosphate (S1P) receptor modulators, of which one has received marketing approval and several others are in clinical development, display promising potential in the treatment of a spectrum of autoimmune diseases.

Areas covered: Administration of S1P₁ receptor modulators leads to functional receptor antagonism triggering sustained inhibition of the egress of lymphocytes from lymphoid organs. First-dose administration is associated with transient cardiovascular effects. We compiled and discussed available pharmacokinetic, pharmacodynamic, and safety data of selective and non-selective S1P receptor modulators that were investigated in recent years.

Expert opinion: 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.

KEYWORDS:

• Autoimmune diseases
• cardiodynamic effect
• fingolimod
• first dose
• lymphocytes
• ponesimod
• S1P₁ receptor modulators

Article highlights

• Selective and non-selective S1P₁ receptor modulators are potent immunomodulators triggering a decrease in specific T and B lymphocyte subsets and have a direct effect on the CNS. They are used and investigated for the treatment of autoimmune disorders.

• These compounds are generally well tolerated but trigger first-dose effects on HR and affect pulmonary and immune systems. Decrease in HR, events of bradycardia, and AV blocks are commonly reported after first-dose administration.

• To mitigate these effects, most of the S1P₁ receptor modulators in development are up-titrated.

• PK properties of these drugs are different. The ones characterized by a rapid elimination show a rapid reversibility of PD effects but may need to be up-titrated initially and after therapy interruptions. The ones with a long half-life have an in-built up-titration but malignancies, infections should be monitored, and pregnancy is more difficult to manage.

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Acknowledgments

The authors wish to express their thanks to Dr M. Boehler for her contribution in the preparation of this paper. The scheme presented in Figure 1(c) and the chemical structures presented in Figure 2 were kindly provided by Dr L. Piali and Dr M Bolli, respectively. Servier Medical Art was used to make the schematic representation in Figure 1(d). All figures and tables are original and have not previously been published elsewhere. We thank Dr. D. D’Ambrosio for a critical review of the manuscript.

Declaration of interest

PE Juif and J Dingemanse are full-time employees at Actelion Pharmaceuticals Ltd, the manufacturer of ponesimod. S Kraehenbuehl was the investigator of some clinical pharmacology studies investigating Actelion compounds (almorexant, macitentan) that were funded by Actelion Pharmaceuticals Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.