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Glibenclamide population pharmacokinetic/pharmacodynamic modeling in South African type 2 diabetic subjects
Virendra Rambiritch1, Poobalan Naidoo2, Goonaseelan Pillai3
1Pharmacology Department, University of KwaZulu-Natal, Durban.
Aim:
To determine the effective dose of glibenclamide by quantifying the dose-response relationship in South African type 2 diabetic patients.
Patients And 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.
Conclusion:
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.
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