Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats
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RESEARCH PAPER
Chase Dosing of Lipid Formulations to Enhance Oral Bioavailability of Nilotinib in Rats Niklas J. Koehl 1 & René Holm 2,3 & Martin Kuentz 4 & Brendan T. Griffin 1
Received: 3 March 2020 / Accepted: 18 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. * Brendan T. Griffin [email protected] 1
School of Pharmacy, University College Cork, Cork, Ireland
2
Drug Product Development, Janssen Research and Development, Johnson & Johnson, Turnhoutseweg 30, 2340 Beerse, Belgium
3
Department of Science and Environment, Roskilde University, 4000 Roskilde, Denmark
4
University of Applied Sciences and Arts Northwestern Switzerland, Institute of Pharma Technology, Muttenz, Switzerland
KEY WORDS brick dust molecule . chase dosing . lipid suspension . lipid based formulation . poorly water-soluble drugs
ABBREVIATIONS MC LC MG TG LBF
Medium chain Long chain Monoglyceride Triglyceride Lipid-based formulation
INTRODUCTION The oral bioavailability of many poorly water-soluble drugs is hindered by low solubility and slow dissolution in the gastrointestinal tract fluids. Lipid based formulations (LBF) are one option to improve the oral bioavailability of poorly water-soluble drugs and have shown numerous commercial success (1,2). In particular, drugs in the Biopharmaceutical Classification System (BCS) class II and IV can benefit from usage of lipid excipients to enhance oral delivery. One of the primary biopharmaceutical advantages of LBFs is the ability to deliver the drug dissolved in lipid excipients and therefore avoiding the drug dissolution process. In addition, LBFs have been
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