title: Reducing Adverse Effects During Drug Development: The Example of Lesogaberan and Paresthesia.
abstract: Lesogaberan, a γ-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.
  
  
  
  This study was a narrative review of the literature and unpublished data.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: AstraZeneca Gothenburg, Sweden. Electronic address: hans.rydholm@astrazeneca.com.
authors.forename: Hans
authors.initials: H
authors.lastname: Rydholm
authors.affiliation: AstraZeneca Gothenburg, Sweden.
authors.forename: Christian
authors.initials: C
authors.lastname: von Corswant
authors.affiliation: AstraZeneca Gothenburg, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Denison
authors.affiliation: AstraZeneca Gothenburg, Sweden.
authors.forename: Jörgen M
authors.initials: JM
authors.lastname: Jensen
authors.affiliation: AstraZeneca Gothenburg, Sweden.
authors.forename: Anders
authors.initials: A
authors.lastname: Lehmann
authors.affiliation: AstraZeneca Gothenburg, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ruth
authors.affiliation: AstraZeneca Gothenburg, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Söderlind
authors.affiliation: AstraZeneca Gothenburg, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Aurell-Holmberg
mesh_terms: D058785:GABA-A Receptor Agonists / Q000009:adverse effects* / Q000627:therapeutic use; D005764:Gastroesophageal Reflux / Q000188:drug therapy; D006801:Humans; D010292:Paresthesia / Q000139:chemically induced*; D010721:Phosphinic Acids / Q000009:adverse effects* / Q000627:therapeutic use; D011437:Propylamines / Q000009:adverse effects* / Q000627:therapeutic use
chemical_list: D058785:GABA-A Receptor Agonists; D010721:Phosphinic Acids; D011437:Propylamines; C545087:lesogaberan
keywords: adverse effect; formulation development; gastroesophageal reflux disease; lesogaberan; paresthesia; γ-aminobutyric acid (GABA)(B) receptor agonist