Next Article in Journal
Telomeres and Longevity: A Cause or an Effect?
Next Article in Special Issue
The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism
Previous Article in Journal
Carcinoembryonic Cell Adhesion-Related Molecule 2 Regulates Insulin Secretion and Energy Balance
Previous Article in Special Issue
The Enigma of Sphingolipids in Health and Disease
Open AccessArticle

Cardiodynamic Interactions between Two S1P1 Receptor Modulators in an Experimental Clinical Setting: Different Pharmacokinetic Properties as an Opportunity to Mitigate First-Dose Heart Rate Effects

Department of Clinical Pharmacology, Idorsia Pharmaceuticals Ltd, Allschwil CH-4123, Switzerland
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(13), 3232; https://doi.org/10.3390/ijms20133232
Received: 24 May 2019 / Revised: 19 June 2019 / Accepted: 28 June 2019 / Published: 1 July 2019
(This article belongs to the Special Issue Sphingolipids: Metabolic Functions and Disorders)
  |  
PDF [1192 KB, uploaded 1 July 2019]
  |  

Abstract

A decrease in heart rate (HR) is a well-established first-dose effect of sphingosine-1-phosphate subtype 1 receptor (S1P1R) modulators. For compounds with a short half-life (t1/2), this can be mitigated by gradual up-titration to therapeutic doses, whereas this is not required for compounds with a long t1/2 due to the less pronounced first-dose-related negative chronotropic effects. Based on this conceptual framework, this mechanistic study investigated whether first-dose HR effects of ponesimod (t1/2 ~32 h) can be mitigated by prior administration of cenerimod (t1/2 ~415 h). Healthy subjects (n = 12) were randomly assigned to active or placebo (2:1 ratio). Active treatment consisted of a single dose of 10 mg ponesimod on Day 1, 18, and 37 and multiple-dose administration of 2 mg once daily cenerimod (Day 9–36). Placebos of cenerimod and ponesimod were used as reference treatment. Cardiodynamic parameters were derived from 24 h Holter electrocardiogram (ECG) assessments on Day 1, 9, 10, 18, 36, and 37. Ponesimod (10 mg) alone triggered a transient mean decrease from baseline in hourly mean HR of 17 bpm. In contrast, decreases of 5.0 and 4.8 bpm were observed when ponesimod was given at near half steady-state (Day 18) or steady-state (Day 37) cenerimod, respectively. Hourly mean HR decreased after first administration of cenerimod and placebo was 7.4 and 4.0 bpm, respectively. Treatment with ponesimod and cenerimod alone or in combination was safe and tolerated. First-dose-related negative chronotropic effects of ponesimod were less pronounced when administered after initiation of cenerimod suggesting mitigation of this class-related liability. View Full-Text
Keywords: S1P1 receptor modulators; first-dose effect; pharmacokinetics S1P1 receptor modulators; first-dose effect; pharmacokinetics
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Juif, P.-E.; Ufer, M.; Dingemanse, J. Cardiodynamic Interactions between Two S1P1 Receptor Modulators in an Experimental Clinical Setting: Different Pharmacokinetic Properties as an Opportunity to Mitigate First-Dose Heart Rate Effects. Int. J. Mol. Sci. 2019, 20, 3232.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top