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Development of a physiologically based pharmacokinetic model for intravenous lenalidomide in mice

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Abstract

Purpose

Lenalidomide is used widely in B-cell malignancies for its immunomodulatory activity. It is primarily eliminated via the kidneys, with a significant proportion of renal elimination attributed to active processes. Lenalidomide is a weak substrate of P-glycoprotein (P-gp), though it is unclear whether P-gp is solely responsible for lenalidomide transport. This study aimed to determine whether the current knowledge of lenalidomide was sufficient to describe the pharmacokinetics of lenalidomide in multiple tissues.

Methods

A physiologically based pharmacokinetic model was developed using the Open Systems Pharmacology Suite to explore the pharmacokinetics of lenalidomide in a variety of tissues. Data were available for mice dosed intravenously at 0.5, 1.5, 5, and 10 mg/kg, with concentrations measured in plasma, brain, heart, kidney, liver, lung, muscle, and spleen. P-gp expression and activity were sourced from the literature.

Results

The model predictions in plasma, liver, and lung were representative of the observed data (median prediction error 13%, − 10%, and 30%, respectively, with 90% confidence intervals including zero), while other tissue predictions showed sufficient similarity to the observed data. Contrary to the data, model predictions for the brain showed no drug reaching brain tissue when P-gp was expressed at the blood–brain barrier. The data were better described by basolateral transporters at the intracellular wall. Local sensitivity analysis showed that transporter activity was the most sensitive parameter in these models for exposure.

Conclusion

As P-gp transport at the blood–brain barrier did not explain the observed brain concentrations alone, there may be other transporters involved in lenalidomide disposition.

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Acknowledgements

The research produced was supported by an Australian Government Research Training Program Scholarship (to JHH). The authors acknowledge that the Australian Centre for Pharmacometrics is an initiative of the Australian Government as part of the National Collaborative Research Infrastructure Strategy. Additional support came from the National Institutes of Health (R01CA201382 to MAP) and an Eli Lilly Fellowship (to DMR).

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Authors and Affiliations

  1. School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, 5001, Australia

    Jim H. Hughes, Richard N. Upton, Stephanie E. Reuter & David J. R. Foster

  2. Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    Darlene M. Rozewski & Mitch A. Phelps

  3. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Darlene M. Rozewski & Mitch A. Phelps

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  1. Jim H. Hughes
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  2. Richard N. Upton
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  4. Darlene M. Rozewski
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Contributions

Participated in research design: JHH, RNU, SER, DMR, MAP, and DJRF. Conducted experiments: DMR. Contributed new reagents or analytical tools: RNU, MAP, and DJRF. Performed data analysis: JHH. Wrote or contributed to the writing of the manuscript: JHH, RNU, SER, DMR, MAP, and DJRF.

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Correspondence to Jim H. Hughes.

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Hughes, J.H., Upton, R.N., Reuter, S.E. et al. Development of a physiologically based pharmacokinetic model for intravenous lenalidomide in mice. Cancer Chemother Pharmacol 84, 1073–1087 (2019). https://doi.org/10.1007/s00280-019-03941-z

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