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Enhancement of Docetaxel Absorption Using Ritonavir in an Oral Milk-Based Formulation

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Abstract

Objective

The current study aimed to develop a novel milk-based formulation of docetaxel, a sparingly soluble antineoplastic agent, administered so far exclusively by the intravenous route and evaluate its oral bioavailability.

Methods

Pre-formulation studies included the determination of docetaxel solubility in water-alcohol mixtures as well as short-term content uniformity experiments of the final formulation. The pharmacokinetic (PK) performance of the developed milk-based formulations was further evaluated in vivo in mice using ritonavir, a potent P-glycoprotein inhibitor, as an absorption enhancer of docetaxel and the marketed intravenous docetaxel formulation, Taxotere®, as a control.

Results

In vivo PK results in mice showed that all the administered oral docetaxel formulations had limited absorption in the absence of ritonavir. On the contrary, ritonavir co-administration given as pre-treatment significantly enhanced oral bioavailability of both the marketed and milk-based docetaxel formulations; an even more marked increase in drug exposure was observed when ritonavir was incorporated within the docetaxel milk-based formulation. The fixed-dose combination also showed a more prolonged absorption of the drug compared to separate administrations.

Conclusions

The current study provides insights for the discovery of a novel milk-based formulation that could potentially serve as an alternative, non-toxic and patient-friendly carrier for an acceptable docetaxel oral chemotherapy.

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Authors and Affiliations

  1. Laboratory of Biopharmaceutics – Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece

    K. Soulele & P. Macheras

  2. Division of Pharmacology-Pharmacotechnology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece

    T. Karampelas & C. Tamvakopoulos

  3. PharmaInformatics Unit, ATHENA Research Center, Artemidos 6 & Epidavrou , 15125, Marousi, Athens, Greece

    P. Macheras

Authors
  1. K. Soulele
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  2. T. Karampelas
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  4. P. Macheras
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Correspondence to P. Macheras.

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Acknowledgments and Disclosures

The authors would like to thank Vianex S.A for the provision of active substances. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. None.

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Soulele, K., Karampelas, T., Tamvakopoulos, C. et al. Enhancement of Docetaxel Absorption Using Ritonavir in an Oral Milk-Based Formulation. Pharm Res 38, 1419–1428 (2021). https://doi.org/10.1007/s11095-021-03085-x

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  • DOI: https://doi.org/10.1007/s11095-021-03085-x

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