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Predicting Intestinal Precipitation—A Case Example for a Basic BCS Class II Drug

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ABSTRACT

Purpose

To investigate the prediction accuracy of in vitro and in vitro/in silico methods for in vivo intestinal precipitation of basic BCS class II drugs in humans.

Methods

Precipitation rate of a model drug substance, AZD0865 (pKa = 6.1; log KD = 4.2), was investigated in vitro using simulated intestinal media, and calculations of the crystallization rates were made with a theoretical model. Human intestinal precipitation was estimated by analysis of pharmacokinetic data from clinical studies at different doses.

Results

All in vitro models predicted rapid drug precipitation, where the intestinal concentration of dissolved AZD0865 at the highest dose tested was expected to decrease to half after less than 20 min. However, there was no indication of precipitation in vivo in humans as there was a dose proportional increase in drug plasma exposure. The theoretical model predicted no significant precipitation within the range of expected in vivo intestinal concentrations.

Conclusions

This study indicated that simple in vitro methods of in vivo precipitation of orally administered bases overpredict the intestinal crystalline precipitation in vivo in humans. Hydrodynamic conditions were identified as one important factor that needs to be better addressed in future in vivo predictive methods.

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ACKNOWLEDGEMENTS

The authors acknowledge the valuable contributions of Dr. Clive Wilder Smith, Dr. Lars-Göran Nilsson, Dr. Jonas Pettersson, Dr. Hans Rydholm and Dr. Mats Ekelund with colleagues for the planning and conduct of the clinical studies. The authors also thank Marie Molander Melin and Dr. Mischa van Hout for the bioanalysis of AZD0865 in the clinical studies. We also thank Kornelia Krumkühler for performance of some of the in vitro experiments, Anders Carlsson for giving advice on HPLC analysis and Jan Westergren for writing the theoretical computational program modelling crystallization rates.

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Authors and Affiliations

  1. Department of Pharmacy, Uppsala University, Box 580, 751 23, Uppsala, Sweden

    Sara Carlert & Hans Lennernäs

  2. Department of Medicines Evaluation, AstraZeneca R&D, 431 83, Mölndal, Sweden

    Anna Pålsson & Gunilla Hanisch

  3. Department of Medicines Development, AstraZeneca R&D, 431 83, Mölndal, Sweden

    Christian von Corswant, Lennart Lindfors & Bertil Abrahamsson

  4. Department of Clinical Pharmacology &DMPK, AstraZeneca R&D, 431 83, Mölndal, Sweden

    Catarina Nilsson

Authors
  1. Sara Carlert
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  2. Anna Pålsson
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  3. Gunilla Hanisch
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  4. Christian von Corswant
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  5. Catarina Nilsson
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  6. Lennart Lindfors
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  7. Hans Lennernäs
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  8. Bertil Abrahamsson
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Corresponding author

Correspondence to Bertil Abrahamsson.

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Carlert, S., Pålsson, A., Hanisch, G. et al. Predicting Intestinal Precipitation—A Case Example for a Basic BCS Class II Drug. Pharm Res 27, 2119–2130 (2010). https://doi.org/10.1007/s11095-010-0213-8

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  • DOI: https://doi.org/10.1007/s11095-010-0213-8

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