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In Vitro Lipolysis Data Does Not Adequately Predict the In Vivo Performance of Lipid-Based Drug Delivery Systems Containing Fenofibrate

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Abstract

The present study investigated the utility of in vitro lipolysis performance indicators drug solubilization and maximum supersaturation ratio (SRM) for their predictive use for the in vivo performance in a minipig model. The commercial Lipanthyl formulation and a series of LbDDS based on identical self-nanoemulsifying drug delivery systems (SNEDDS) containing 200 mg of fenofibrate, either dissolved or suspended, were subjected to combined gastric (pH 2) and intestinal (pH 6.5) in vitro lipolysis. Based on the solubilization profiles and SRM the rank-order SNEDDS (75% drug load) > super-SNEDDS (150% drug load, dissolved) = SNEDDS suspension (150% drug load, partially suspended) > Lipanthyl was established, with an increased likelihood of drug precipitation above SRM > 3. The in vitro performance, however, was not reproduced in vivo in a minipig model as the mean plasma concentration over time curves of all LbDDS were comparable, independent of the initial physical state of the drug. There was no correlation between the area under the solubilization-time curves (AUC in vitro ) of the intestinal step and the AUC in vivo . The study suggests careful interpretation of in vitro performance criteria and revision of LbDDS optimization towards increased solubilization.

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Acknowledgment

The authors would like to thank the personnel at the Lundbeck animal facilities for their skillful handling of the animals and support for this study.

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Authors and Affiliations

  1. Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100, Denmark

    Nicky Thomas, Katharina Richter, Thomas B. Pedersen, Anette Müllertz & Thomas Rades

  2. Ian Wark Research Institute, University of South Australia, Mawson Lakes Campus, Mawson Lakes, SA, 5095, Australia

    Nicky Thomas & Katharina Richter

  3. Biologics and Pharmaceutical Science, H.Lundbeck A/S, Ottiliavej 9, Valby, 2500, Denmark

    René Holm

  4. Bioneer:FARMA, Danish Drug Development Center, Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, Copenhagen, 2100, Denmark

    Anette Müllertz

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  1. Nicky Thomas
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Correspondence to Anette Müllertz.

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Thomas, N., Richter, K., Pedersen, T.B. et al. In Vitro Lipolysis Data Does Not Adequately Predict the In Vivo Performance of Lipid-Based Drug Delivery Systems Containing Fenofibrate. AAPS J 16, 539–549 (2014). https://doi.org/10.1208/s12248-014-9589-4

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