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Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats

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Abstract

Purpose

Lipid-based formulations (LBF) have shown oral bioavailability enhancement of lipophilic drugs, but not necessarily in the case of hydrophobic drugs. This study explored the potential of lipid vehicles to improve the bioavailability of the hydrophobic drug nilotinib comparing a chase dosing approach and lipid suspensions.

Methods

Nilotinib in vivo bioavailability in rats was determined after administering an aqueous suspension chase dosed with blank olive oil, Captex 1000, Peceol or Capmul MCM, respectively. Absolute bioavailability was determined (relative to an intravenous formulation). Pharmacokinetic parameters were compared to lipid suspensions.

Results

Compared to the lipid suspensions, the chase dosed lipids showed a 2- to 7-fold higher bioavailability. Both long chain chase dosed excipients also significantly increased the bioavailability up to 2-fold compared to the aqueous suspension. Deconvolution of the pharmacokinetic data indicated that chase dosing of nilotinib resulted in prolonged absorption compared to the aqueous suspension.

Conclusion

Chase dosed LBF enhanced the in vivo bioavailability of nilotinib. Long chain lipids showed superior performance compared to medium chain lipids. Chase dosing appeared to prolong the absorption phase of the drug. Therefore, chase dosing of LBF is favourable compared to lipid suspensions for ‘brick dust’ molecules such as nilotinib.

The potential of bio-enabling lipid vehicles, administered via chase dosing and lipid suspensions, has been evaluated as an approach to enhance oral bioavailability of nilotinib.

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Abbreviations

MC:

Medium chain

LC:

Long chain

MG:

Monoglyceride

TG:

Triglyceride

LBF:

Lipid-based formulation

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ACKNOWLEDGMENTS AND DISCLOSURES

This work was kindly supported by funding from the Horizon 2020 Marie Sklodowska-Curie Innovative Training Networks programme under grant agreement No. 674909. The authors are part of the PEARRL European Training network, which is funded under this MSCA programme.

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Authors and Affiliations

  1. School of Pharmacy, University College Cork, Cork, Ireland

    Niklas J. Koehl & Brendan T. Griffin

  2. Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340, Beerse, Belgium

    René Holm

  3. Department of Science and Environment, Roskilde University, 4000, Roskilde, Denmark

    René Holm

  4. University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland

    Martin Kuentz

Authors
  1. Niklas J. Koehl
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  2. René Holm
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  4. Brendan T. Griffin
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Correspondence to Brendan T. Griffin.

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Koehl, N.J., Holm, R., Kuentz, M. et al. Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats. Pharm Res 37, 124 (2020). https://doi.org/10.1007/s11095-020-02841-9

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  • DOI: https://doi.org/10.1007/s11095-020-02841-9

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