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

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.