Population pharmacokinetic modeling of glibenclamide in poorly controlled South African type 2 diabetic subjects
Authors Rambiritch V, Naidoo P, Maharaj B, Pillai G
Received 17 December 2015
Accepted for publication 9 February 2016
Published 12 July 2016 Volume 2016:8 Pages 83—92
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Professor Arthur Frankel
Virendra Rambiritch,1 Poobalan Naidoo,2 Breminand Maharaj,1 Goonaseelan Pillai3
1University of KwaZulu-Natal, Durban, 2Department of Internal Medicine, RK Khan Regional Hospital, Chatsworth, South Africa; 3Novartis Pharma AG, Basel, Switzerland
Aim: The aim of this study was to describe the pharmacokinetics (PK) of glibenclamide in poorly controlled South African type 2 diabetic subjects using noncompartmental and model-based methods.
Methods: A total of 24 subjects with type 2 diabetes were administered increasing doses (0 mg/d, 2.5 mg/d, 5 mg/d, 10 mg/d, and 20 mg/d) of glibenclamide daily at 2-week intervals. Plasma glibenclamide, glucose, and insulin determinations were performed. Blood sampling times were 0 minute, 30 minutes, 60 minutes, 90 minutes, and 120 minutes (post breakfast sampling) and 240 minutes, 270 minutes, 300 minutes, 330 minutes, 360 minutes, and 420 minutes (post lunch sampling) on days 14, 28, 42, 56, and 70 for doses of 0 mg, 2.5 mg, 5.0 mg, 10 mg, and 20 mg, respectively. Blood sampling was performed after the steady state was reached. A total of 24 individuals in the data set contributed to a total of 841 observation records. The PK was analyzed using noncompartmental analysis methods, which were implemented in WinNonLin®, and population PK analysis using NONMEM®. Glibenclamide concentration data were log transformed prior to fitting.
Results: A two-compartmental disposition model was selected after evaluating one-, two-, and three-compartmental models to describe the time course of glibenclamide plasma concentration data. The one-compartment model adequately described the data; however, the two-compartment model provided a better fit. The three-compartment model failed to achieve successful convergence. A more complex model, to account for enterohepatic recirculation that was observed in the data, was unsuccessful.
Conclusion: In South African diabetic subjects, glibenclamide demonstrates linear PK and was best described by a two-compartmental model. Except for the absorption rate constant, the other PK parameters reported in this study are comparable to those reported in the scientific literature. The study is limited by the small study sample size and inclusion of poorly controlled type 2 diabetic subjects.
Keywords: type 2 diabetes mellitus, glibenclamide, pharmacokinetics, compartmental, NONMEM model
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