European Journal of Clinical Pharmacology

, Volume 74, Issue 12, pp 1593–1604 | Cite as

Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects

  • Anne GardinEmail author
  • Cathy Gray
  • Srikanth Neelakantham
  • Felix Huth
  • Antonia M. Davidson
  • Swati Dumitras
  • Eric Legangneux
  • Kasra Shakeri-Nejad
Pharmacokinetics and Disposition



To assess the potential pharmacokinetic (PK) interactions between siponimod and rifampin, a strong CYP3A4/moderate CYP2C9 inducer, in healthy subjects.


This was a confirmatory, open-label, multiple-dose two-period study in healthy subjects (aged 18–45 years). In Period 1 (Days 1–12), siponimod was up-titrated from 0.25 to 2 mg over 5 days (Days 1–6) followed by 2 mg once daily on days 7–12. In Period 2, siponimod 2 mg qd was co-administered with rifampin 600 mg qd (Days 13–24). Primary assessments included PK of siponimod (Days 12 and 24; maximum steady-state plasma concentration [Cmax,ss], median time to achieve Cmax,ss [Tmax, ss], and area under the curve at steady state [AUCtau,ss]). Key secondary assessments were PK of M3 and M5 metabolites, and safety/tolerability including absolute lymphocyte count (ALC).


Of the 16 subjects enrolled (age, mean ± standard deviation [SD] 31 ± 8.3 years; men, n = 15), 15 completed the study. In Period 1, siponimod geometric mean Cmax,ss (28.6 ng/mL) was achieved in 4 h (median Tmax,ss; range, 1.58–8.00) and the geometric mean AUCtau,ss was 546 h × ng/mL. In Period 2, the siponimod geometric mean Cmax,ss and AUCtau,ss decreased to 15.7 ng/mL and 235 h × ng/mL, respectively; median Tmax remained unchanged (4 h). Rifampin co-administration increased M3 Cmax,ss by 53% while M5 Cmax,ss remained unchanged. The AUCtau,ss of M3 and M5 decreased by 10% and 37%, respectively. The majority of adverse events reported were mild, with a higher frequency during Period 2 (86.7%) versus Period 1 (50%). The mean ALC increased slightly under rifampin co-administration but remained below 1.0 × 109/L.


The study findings suggest that in the presence of rifampin, a strong CYP3A4/moderate CYP2C9 inducer, siponimod showed significant decrease in Cmax,ss (45%) and AUCtau,ss (57%) in healthy subjects.


Siponimod Rifampin Pharmacokinetics Drug–drug interactions Healthy subjects 



The authors thank subjects and participating centres involved in study. The authors would also like to acknowledge Sivaram Vedantam and Anuja Shah of Novartis Healthcare Pvt. Ltd. Hyderabad, India, for providing medical writing support, which encompassed preparing the manuscript, formatting, referencing, preparing tables and figures, incorporating authors’ revisions, finalising, and submission, all under the direction of the authors. In keeping with the guidelines of the International Committee of Medical Journal Editors, all authors have contributed significantly to the study and were thoroughly involved in the critical review of the manuscript for important intellectual content. All authors have reviewed and approved the final draft for submission.

Author contributions

Anne Gardin and Kasra Shakeri-Nejad conceptualised and designed the studies, analysed and interpreted the study data. Cathy Gray was involved in study design and study execution. Srikanth Neelakantham conceptualised and designed the studies, analysed and interpreted the study data, and conducted statistical analysis of the data. Felix Huth, Antonia M. Davidson, and Eric Legangneux were involved in conceptualising and designing of studies, and acquisition and analysis of data. All authors made significant contribution to data interpretation and review of the manuscript.


The study was funded by Novartis Pharma AG, Basel, Switzerland.

Compliance with ethical standards

Conflicts of interest

Antonia M. Davidson is a principal investigator at the PPD Phase 1 Clinic, Austin, TX, USA.

Anne Gardin, Cathy Gray, Srikanth Neelakantham, Felix Huth, Swati Dumitras, Eric Legangneux, and Kasra Shakeri-Nejad are employees of Novartis.

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Anne Gardin
    • 1
    Email author
  • Cathy Gray
    • 2
  • Srikanth Neelakantham
    • 3
  • Felix Huth
    • 1
  • Antonia M. Davidson
    • 4
  • Swati Dumitras
    • 1
  • Eric Legangneux
    • 1
  • Kasra Shakeri-Nejad
    • 1
  1. 1.Novartis Institutes for BioMedical ResearchBaselSwitzerland
  2. 2.Novartis Pharmaceuticals CorporationEast HanoverUSA
  3. 3.Novartis Healthcare Pvt. Ltd.HyderabadIndia
  4. 4.PPDAustinUSA

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