Pharmacokinetics and safety of oral glyburide in dogs with acute spinal cord injury.

Nick Jeffery,Virginia Fajt,Megan Konarik,Travis Mays,C Elizabeth Boudreau

doi:10.7717/peerj.4387

Abstract

BackgroundGlyburide (also known as glibenclamide) is effective in reducing the severity of tissue destruction and improving functional outcome after experimental spinal cord injury in rodents and so has promise as a therapy in humans. There are many important differences between spinal cord injury in experimental animals and in human clinical cases, making it difficult to introduce new therapies into clinical practice. Spinal cord injury is also common in pet dogs and requires new effective therapies, meaning that they can act as a translational model for the human condition while also deriving direct benefits from such research. In this study we investigated the pharmacokinetics and safety of glyburide in dogs with clinical spinal cord injury.MethodsWe recruited dogs that had incurred an acute thoracolumbar spinal cord injury within the previous 72 h. These had become acutely non-ambulatory on the pelvic limbs and were admitted to our veterinary hospitals to undergo anesthesia, cross sectional diagnostic imaging, and surgical decompression. Oral glyburide was given to each dog at a dose of 75 mcg/kg. In five dogs, we measured blood glucose concentrations for 10 h after a single oral dose. In six dogs, we measured serum glyburide and glucose concentrations for 24 h and estimated pharmacokinetic parameters to estimate a suitable dose for use in a subsequent clinical trial in similarly affected dogs.ResultsNo detrimental effects of glyburide administration were detected in any participating dog. Peak serum concentrations of glyburide were attained at a mean of 13 h after dosing, and mean apparent elimination half-life was approximately 7 h. Observed mean maximum plasma concentration was 31 ng/mL. At the glyburide dose administered there was no observable association between glyburide and glucose concentrations in blood.DiscussionOur data suggest that glyburide can be safely administered to dogs that are undergoing anesthesia, imaging and surgery for treatment of their acute spinal cord injury and can attain clinically-relevant serum concentrations without developing hazardous hypoglycemia. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25–50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury.

Highlights

Despite extensive research on the mechanisms mediating the transition from traumatic spinal cord injury to tissue destruction, an unequivocally-accepted medical intervention for reduction in tissue destruction has not been introduced into clinical medicine
There is a role for many models to achieve this aim: for instance, laboratory models of spinal cord injury in primates are important in investigation of strategies to improve hand use (Salegio et al, 2016) and pig models are useful for making measurements of intradural pressure following experimental spinal cord injury (Streijger et al, 2017)
After receiving informed owner consent, each dog received 75 mcg/kg glyburide orally; the dose was chosen based on previous safety studies in dogs and the dosages given in similar human clinical trials

Summary

Introduction

Despite extensive research on the mechanisms mediating the transition from traumatic spinal cord injury to tissue destruction, an unequivocally-accepted medical intervention for reduction in tissue destruction has not been introduced into clinical medicine This failure is especially surprising bearing in mind the large number of interventions that have been effective in experimental rodent models (Kwon et al, 2011; Tetzlaff et al, 2011). An important difference between laboratory models and human spinal cord injury is the heterogeneity of clinical patients; notably they vary in genetics, age, comorbidities and time delay between injury and access to therapy Such heterogeneity introduces several sources of variation into outcome measures and implies that apparent effectiveness of an intervention in the laboratory may not be apparent when applied in clinical patients. Serum glyburide concentrations achieved in this study suggest that a loading dose of 150 mcg/kg followed by repeat doses of 75 mcg/kg at 8-hourly intervals would lead to serum glyburide concentrations of 25–50 ng/mL within an acceptably short enough period after oral administration to be appropriate for a clinical trial in canine spinal cord injury

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