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Pharmacokinetics and Tolerability of Exenatide Delivered by 7-Day Continuous Subcutaneous Infusion in Healthy Volunteers

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Abstract

Introduction

Small peptides are approved as treatments for type 2 diabetes mellitus and may have utility in metabolic diseases. These peptides often have short half-lives requiring delivery either as a sustained-release formulation or via a device. The opportunity to study their pharmacokinetics using simple solution formulations delivered by continuous subcutaneous infusion may facilitate the drug development process.

Methods

Here, we investigated the systemic exposure of an exemplar peptide (exenatide) when infused in healthy subjects using a Paradigm® Revel™ insulin infusion pump (Medtronic MiniMed). Four infusion regimens were tested: Constant 24-h infusion (16.5 μg/day), constant 7-day infusion (25.5 μg/day in Cohort 2), and two different 7-day escalation regimens (ranging from 7 to 58.5 μg/day in Cohort 1 and 25.5–58.5 μg/day in Cohort 3).

Results

While the overall exenatide pharmacokinetics were in line with those expected, the observed within-subject concentration variability was considerable.

Conclusion

Our work identifies sources of potential pharmacokinetic variability relating to the method of delivery and the drug’s formulation that will be valuable to investigators contemplating the delivery of peptides via insulin infusion pumps.

Funding

GlaxoSmithKline.

Trial registration: ClinicalTrials.gov number, NCT01857895.

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Acknowledgments

This study (ClinicalTrials.gov number, NCT01857895) and the article processing charges associated with this publication have been sponsored by GlaxoSmithKline. We thank the investigator and subjects who participated in the study and Rebecca Hodge, Ella Kersey, Malcolm Young, and Steve Stagliano (Medtronic Inc.) for their valuable input. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.

Conflict of interest

Georgios Vlasakakis was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Susan L. Johnson was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Jiang Lin was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Xiaozhou Yao was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Christopher J. Gruenloh was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. John P. Chism was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company. Derek J. Nunez was an employee of GlaxoSmithKline at the time of this publication and has/had stock/stock options in the company.

Compliance with ethics guidelines

The study protocol and one amendment, the informed consent, and other relevant information were reviewed and approved by a GlaxoSmithKline protocol review group and an institutional review board (Aspireirb, 11491 Woodside Ave, Santee, CA 92071), in accordance with the International Conference on Harmonization Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Written informed consent was obtained from each subject prior to the performance of any study-specific procedures.

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Authors and Affiliations

  1. GlaxoSmithKline Research and Development, Stockley Park West, Uxbridge, London, UB11 1BT, UK

    Georgios Vlasakakis

  2. GlaxoSmithKline Research and Development, 5 Moore Dr, Research Triangle Park, NC, USA

    Susan L. Johnson, Jiang Lin, Xiaozhou Yao, Christopher J. Gruenloh, John P. Chism & Derek J. Nunez

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  1. Georgios Vlasakakis
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  2. Susan L. Johnson
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  3. Jiang Lin
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  7. Derek J. Nunez
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Corresponding author

Correspondence to Georgios Vlasakakis.

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Vlasakakis, G., Johnson, S.L., Lin, J. et al. Pharmacokinetics and Tolerability of Exenatide Delivered by 7-Day Continuous Subcutaneous Infusion in Healthy Volunteers. Adv Ther 32, 650–661 (2015). https://doi.org/10.1007/s12325-015-0222-4

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  • DOI: https://doi.org/10.1007/s12325-015-0222-4

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