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Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

To evaluate the PK and safety of siponimod, a substrate of CYP2C9/3A4, in the presence or absence of a CYP3A4 inhibitor, itraconazole.

Methods

This was an open-label study in healthy subjects (aged 18–50 years; genotype: CYP2C9 *1*2 [cohort 1; n = 17] or *1*3 [cohort 2; n = 13]). Subjects received siponimod 0.25-mg single dose in treatment period 1 (days 1–14), itraconazole 100 mg twice daily in treatment period 2 (days 15–18), and siponimod 0.25-mg single dose (day 19) with itraconazole until day 31 (cohort 1) or day 35 (cohort 2) in treatment period 3. PK of siponimod alone and with itraconazole and safety were assessed.

Results

Overall, 29/30 subjects completed the study. In treatment period 1, geometric mean AUCinf, T1/2, and median Tmax were higher while systemic clearance was lower in cohort 2 than cohort 1. In treatment period 3, siponimod AUC decreased by 10% (geo-mean ratio [90% confidence intervals]: 0.90 [0.84; 0.96]) and 24% (0.76 [0.69; 0.82]) in cohorts 1 and 2, respectively. Siponimod Cmax was similar between treatment periods 1 and 3. In both cohorts, the Cmax and AUC of the metabolites (M17, M3, and M5) decreased in the presence of itraconazole. All adverse events were mild.

Conclusions

The minor albeit significant reduction in plasma exposure of siponimod and its metabolites by itraconazole was unexpected. While the reason is unclear, the results suggest that coadministration of the two drugs would not cause a considerable increase of siponimod exposure independent of CYP2C9 genotype.

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Acknowledgments

The authors would like to acknowledge Stuart Harris (the principal investigator) who contributed to the protocol development and data analysis, Vikram Kanmathareddy who was the trial programmer and Subhajit Choudhury for his assistance/contribution to the statistical design and analysis. They would also like to acknowledge Arshjyoti Singh 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, finalizing and submission, all under the direction of the authors and Sivaram Vedantam (Novartis Healthcare Pvt. Ltd.) for review support. All authors edited the manuscript for intellectual content, provided guidance during manuscript development, and approved the final version submitted for publication.

Funding

This study was funded by Novartis Pharma AG, Switzerland.

Author information

Authors and Affiliations

  1. Novartis Institutes for Biomedical Research, Basel, Switzerland

    Anne Gardin, Kasra Shakeri-Nejad, Andrea Feller, Felix Huth & Swati Dumitras

  2. Novartis Healthcare Pvt. Ltd., Hyderabad, India

    Srikanth Neelakantham

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  1. Anne Gardin
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Contributions

Anne Gardin (pharmacokinetics) and Kasra Shakeri-Nejad (medical, safety) conceptualized and designed the study, contributed to the protocol development and study conduct, analyzed and interpreted the study data, and contributed to the study report preparation. Andrea Feller contributed to the protocol development, study conduct, and study report preparation. Felix Huth contributed to the conceptualization and interpretation of the data. Srikanth Neelakantham was the trial statistician. Swati Dumitras supported the conceptualization of the study, provided critical revision of the manuscript for the content, and supervised the overall research. All authors made a significant contribution to data interpretation and review of the manuscript.

Corresponding author

Correspondence to Anne Gardin.

Ethics declarations

The study was conducted at two centers namely, SeaView Research, Inc., Miami, Florida, USA and SeaView Jacksonville, LLC Jacksonville, Florida, USA. The study protocol and subject consent forms were reviewed and approved by the Schulman Institutional Review Board, Cincinnati OH, USA. The study was conducted according to the ethical principles of the Declaration of Helsinki [30] and designed in compliance with the FDA guidelines for industry on Drug Interaction Studies-Study Design, Data Analysis, Implications for Dosing and Labeling Recommendation [21].

Conflict of interest

Anne Gardin, Andrea Feller, Felix Huth, Srikanth Neelakantham, Swati Dumitras, 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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Gardin, A., Shakeri-Nejad, K., Feller, A. et al. Siponimod pharmacokinetics, safety, and tolerability in combination with the potent CYP3A4 inhibitor itraconazole in healthy subjects with different CYP2C9 genotypes. Eur J Clin Pharmacol 75, 1565–1574 (2019). https://doi.org/10.1007/s00228-019-02729-7

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