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Evaluation of an Innovative Population Pharmacokinetic-Based Design for Behavioral Pharmacodynamic Endpoints

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Abstract

Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining three studies into a single experimental design and using sparse PK sampling in the same animals as for PD. A refined dosing strategy was applied for a muscarinic agonist, AZD6088, using the rat spinal nerve ligation heat hyperalgesia model. PD measurements were performed on day 1, 3, 5 and 8. Two PK samples per day were taken day 2 and 4. In a separate control group, PD measurements were performed on rats without PK sampling. Data was analyzed using a population approach in NONMEM. The animals produced a consistent and reproducible response irrespective of day of testing suggesting that blood sampling on alternate days did not interfere with the PD responses. A direct concentration–effect relationship with good precision was established and no tolerance development was observed. The new design combining three studies into one and eliminating a satellite PK group realized substantial savings compared to the old design; animal use was reduced by 58% and time required to generate results was reduced by 55%. The design described here delivers substantial savings in animal lives, time, and money whilst still delivering a good quality and precise description of the PKPD relationship.

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Acknowledgments

We are grateful to Denis Projean and Louis Matthyssen for their excellent contribution and technical assistance.

Conflict of Interest

The authors state that there are no conflicts of interest in respect to the work reported in this paper.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, AstraZeneca R&D Södertälje, 151 85, Södertälje, Sweden

    Anders Viberg

  2. AstraZeneca R&D Montreal, 7171 Frederick Banting, Montreal, Quebec, H4S 1Z9, Canada

    Giovanni Martino, Etienne Lessard & Jennifer M. A. Laird

  3. Department of Pharmacology & Therapeutics, and Alan Edwards Centre for Research on Pain, McGill University, Montreal, Canada

    Jennifer M. A. Laird

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  1. Anders Viberg
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  2. Giovanni Martino
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  3. Etienne Lessard
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  4. Jennifer M. A. Laird
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Correspondence to Anders Viberg.

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Viberg, A., Martino, G., Lessard, E. et al. Evaluation of an Innovative Population Pharmacokinetic-Based Design for Behavioral Pharmacodynamic Endpoints. AAPS J 14, 657–663 (2012). https://doi.org/10.1208/s12248-012-9380-3

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  • DOI: https://doi.org/10.1208/s12248-012-9380-3

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