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A phase I study of the effect of repeated oral doses of pantoprazole on the pharmacokinetics of a single dose of fedratinib in healthy male subjects

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Abstract

Purpose

Fedratinib, an oral, selective Janus kinase 2 inhibitor with activity against both wild-type and mutant Janus kinase 2, has pH-dependent solubility, with free solubility at pH 1. Concomitant administration of drugs that reduce gastric acid secretion, such as pantoprazole, may decrease the absorption of fedratinib and affect patient outcomes. The aim of this study was to evaluate the impact of 7-day repeated 40-mg doses of pantoprazole on the pharmacokinetic (PK) properties of a single 500-mg dose of fedratinib in healthy male subjects.

Methods

In this phase I, single-center, open-label, two-period, two-treatment, fixed-sequence crossover study, healthy male subjects were administered a single dose of fedratinib 500 mg on day 1 in Period 1, followed by pantoprazole 40 mg daily for 7 days (day 1 to day 7) and a single dose of fedratinib 500 mg on day 7 in Period 2. After the discontinuation of nine subjects due to vomiting, the protocol was amended to provide ondansetron as antiemetic prophylaxis to an additional ten enrolled subjects.

Results

Twenty-six subjects were included. Repeated doses of pantoprazole 40 mg resulted in clinically insignificant increases in fedratinib exposure. Maximum plasma concentration increased by 1.09-fold and area under the plasma concentration–time curve from time 0 to infinity increased by 1.15-fold. All treatment-emergent adverse events were mild or moderate, except for one instance of neutropenia, which was considered unrelated to study intervention.

Conclusion

Coadministration with pantoprazole did not have clinically meaningful effects on fedratinib PK. No new or unexpected safety signals were observed with fedratinib.

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Funding

The clinical trial reported in this manuscript was sponsored by Sanofi. Medical writing support was provided by Shawn Vahabzadeh, PharmD, of MediTech Media and funded by Bristol Myers Squibb.

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Authors and Affiliations

  1. Bristol Myers Squibb, 556 Morris Ave, Summit, NJ, 07901, USA

    Ken Ogasawara, Maria Palmisano & Gopal Krishna

  2. Altasciences/Vince and Associates, Overland Park, KS, USA

    Bradley Vince

  3. Sanofi, Bridgewater, NJ, USA

    Christine Xu & Meng Zhang

Authors
  1. Ken Ogasawara
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  2. Bradley Vince
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  3. Christine Xu
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  4. Meng Zhang
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  5. Maria Palmisano
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  6. Gopal Krishna
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Corresponding author

Correspondence to Gopal Krishna.

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Conflict of interest

KO, MP, and GK are employed by and hold equity ownership in Bristol Myers Squibb. CX and MZ are employed by and hold equity ownership in Sanofi. BV has nothing to disclose.

Ethical approval

All study procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments.

Informed consent

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

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Ogasawara, K., Vince, B., Xu, C. et al. A phase I study of the effect of repeated oral doses of pantoprazole on the pharmacokinetics of a single dose of fedratinib in healthy male subjects. Cancer Chemother Pharmacol 85, 995–1001 (2020). https://doi.org/10.1007/s00280-020-04074-4

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  • DOI: https://doi.org/10.1007/s00280-020-04074-4

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