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A randomized, crossover phase 1 study to assess the effects of formulation (capsule vs tablet) and meal consumption on the bioavailability of dovitinib (TKI258)

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Abstract

Purpose

This 2-arm crossover study compared the relative bioavailability of two dovitinib (TKI258) formulations [anhydrate clinical service form (CSF) capsule and monohydrate final market image (FMI) tablet; Arm 1] and determined the effect of food on dovitinib exposure (Arm 2).

Methods

Patients with advanced solid tumors, excluding breast cancer, were enrolled in 1 of the 2 arms of the study. Patients in Arm 1 were randomized to a single 500-mg dose of CSF capsule or FMI tablet followed by 7 days of rest and 500 mg of the other formulation. Patients in Arm 2 received 300 mg of FMI tablet daily and were randomized to follow 1 of 6 meal sequences, each with 3 prandial conditions: low fat (LF), high fat (HF), or no meal (NM).

Results

In Arm 1 (n = 21), 17 patients were evaluable. FMI tablet compared with CSF capsule showed only slight reductions in the adjusted geometric means for area under the plasma concentration–time curve (AUClast; 3 %) and maximum plasma concentration (C max; 1 %). In Arm 2 (n = 42), 19 patients were evaluable. HF meal versus NM showed a 9 % decrease in the adjusted geometric mean for AUClast and an 18 % decrease for C max. Comparison of LF meal versus NM showed a 1 % decrease for AUClast and a 10 % decrease for C max. Common adverse events suspected to be study drug related included vomiting, diarrhea, nausea, and fatigue.

Conclusions

Dovitinib FMI tablet had similar systemic exposure to the CSF capsule and was not affected by food.

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Acknowledgments

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Swarupa Kulkarni, Suraj Anand, Alaeddin Homsi, and Mariama Diallo for their contributions to the study and Julie M. Shilane, PhD, and Peter J. Simon, PhD, for medical editorial assistance with this manuscript. This study was funded by Novartis Pharmaceuticals Corporation.

Conflict of Interest

Dr. Infante discloses a consultant/advisory role with Novartis (no personal compensation; institution is compensated). Dr. Ramanathan discloses research funding from Novartis. Dr. George discloses remuneration from Novartis, Pfizer, Sanofi and Dendreon; consultant/advisory role with Astellas, AVEO, Bayer, Dendreon, Exelixis, Genentech, Medivation, Novartis, Pfizer, Sanofi, Viamet; funding from BMS, Dendreon, Exelixis, Genentech, Glaxo Smith Kline, Janssen, Millennium, Novartis, Pfizer. Eugene Tan discloses stock ownership in Novartis. Michelle Quinlan has nothing to disclose. Angela Liu and Jeffrey Scott disclose remuneration from and stock ownership in Novartis. Dr. Sharma discloses a consultant/advisory role with Novartis, stock ownership in Salarius, Beta Cat and ConverGene, and funding from Novartis.

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Authors and Affiliations

  1. Sarah Cannon Research Institute, Nashville, TN, USA

    Jeffrey R. Infante

  2. Virginia G. Piper Cancer Center, Scottsdale, AZ, USA

    Ramesh K. Ramanathan

  3. Duke University School of Medicine, Durham, NC, USA

    Daniel George

  4. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Eugene Tan, Michelle Quinlan, Angela Liu & Jeffrey W. Scott

  5. Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr, Rm 3360, Salt Lake City, UT, 84112, USA

    Sunil Sharma

Authors
  1. Jeffrey R. Infante
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  2. Ramesh K. Ramanathan
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  3. Daniel George
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  4. Eugene Tan
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  5. Michelle Quinlan
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  6. Angela Liu
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  7. Jeffrey W. Scott
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  8. Sunil Sharma
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Corresponding author

Correspondence to Sunil Sharma.

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Infante, J.R., Ramanathan, R.K., George, D. et al. A randomized, crossover phase 1 study to assess the effects of formulation (capsule vs tablet) and meal consumption on the bioavailability of dovitinib (TKI258). Cancer Chemother Pharmacol 75, 729–737 (2015). https://doi.org/10.1007/s00280-015-2681-3

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  • DOI: https://doi.org/10.1007/s00280-015-2681-3

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