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Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia

Journal article
Authors H. Rydholm
Fredrik von Corswant
H. Denison
J. M. Jensen
Anders Lehmann
Magnus Ruth
E. Soderlind
A. Aurell-Holmberg
Published in Clinical Therapeutics
Volume 38
Issue 4
Pages 946-960
ISSN 0149-2918
Publication year 2016
Published at Institute of Neuroscience and Physiology
Institute of Clinical Sciences, Department of Otorhinolaryngology
Pages 946-960
Language en
Keywords gamma-aminobutyric acid (GABA)(B) receptor agonist, adverse-effect, formulation development, gastroesophageal-reflux disease, esophageal sphincter relaxations, pump, inhibitor therapy, controlled-trial, volunteers, mechanism, symptoms, agonist, Pharmacology & Pharmacy
Subject categories Clinical Medicine


Purpose: Lesogaberan, a gamma-aminobutyric acid (GABA)(B) receptor agonist, was developed for the treatment of gastroesophageal reflux disease in patients with a partial response to proton pump inhibitor therapy. A high prevalence of paresthesia was observed in healthy individuals after dosing with lesogaberan in early-phase clinical trials. The aim of this review was to gain further insight into paresthesia caused by lesogaberan by summarizing the relevant preclinical and clinical data. Methods: This study was a narrative review of the literature and unpublished data. Findings: The occurrence of paresthesia may depend on the route or rate of drug administration; several studies were conducted to test this hypothesis, and formulations were developed to minimize the occurrence of paresthesia. Phase I clinical studies showed that, in healthy individuals, paresthesia occurred soon after administration of lesogaberan in a dose-dependent manner regardless of the route of administration. The occurrence of paresthesia could be decreased by fractionating the dose or reducing the rate of administration. These findings suggest that the initial rate of absorption plays an important part in the development of paresthesia. Modified-release formulations minimize the occurrence of paresthesia while retaining the anti-reflux activity of the drug, as measured by esophageal pH and the number of transient lower esophageal sphincter relaxations. Implications: The development of lesogaberan was halted because the effect on gastroesophageal reflux disease symptoms observed in Phase II studies was not considered clinically meaningful in the target patient population. Nevertheless, it is an example of successful formulation development designed to minimize the occurrence of a compound's adverse effect while retaining its pharmacodynamic action. (C) 2016 Elsevier HS Journals, Inc. All rights reserved.

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