title: Glibenclamide population pharmacokinetic/pharmacodynamic modeling in South African type 2 diabetic subjects.
abstract: OBJECTIVE
  To determine the effective dose of glibenclamide by quantifying the dose-response relationship in South African type 2 diabetic patients.
  
  
  METHODS
  A total of 24 type 2 diabetic patients participated in a glibenclamide dose-escalation study during which glibenclamide, glucose, and insulin concentrations were quantified, while the dose of glibenclamide was progressively increased. All except four subjects contributed data on all dose-escalation steps; however, data from all 24 patients were included in the model-based analysis. Pharmacokinetic/pharmacodynamic (PKPD) relationships were modeled using the software Nonmem®. Six models were utilized to explore the effect of alternative glibenclamide dose and plasma concentration inputs on various metrics of glucose response.
  
  
  RESULTS
  Six models adequately described the experimental data. The effective dose for a glucose-lowering effect suggested by PKPD modeling is less than 5 mg/day. Doses beyond 5 mg/day do not meaningfully add to glibenclamide effects on blood-glucose response.
  
  
  CONCLUSIONS
  The effective dose of glibenclamide, suggested by PKPD modeling, is less than 5 mg/day. Higher doses of glibenclamide, eg, 15 mg/day as originally recommended by the manufacturer, do not produce further decrease in the blood glucose level but may predispose the patients to adverse effects.
authors.affiliation: Pharmacology Department, University of KwaZulu-Natal, Durban.
authors.forename: Virendra
authors.initials: V
authors.lastname: Rambiritch
authors.affiliation: Department of Internal Medicine, RK Khan Regional Hospital, Chatsworth, South Africa.
authors.forename: Poobalan
authors.initials: P
authors.lastname: Naidoo
authors.affiliation: Scientific Capability Development, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Goonaseelan
authors.initials: G
authors.lastname: Pillai
keywords: Nonmem; dose–response relationships; glibenclamide; pharmacokinetic/pharmacodynamic modeling; type 2 diabetes