Glibenclamide population pharmacokinetic/pharmacodynamic modeling in South African type 2 diabetic subjects

Figures & data

Figure 1 Plots of observed glucose concentrations (open circles), population model predictions (dotted line), and individual model predictions (solid line) from the dose–fasting glucose concentration PKPD model for glucose response to glibenclamide.

Notes: Each cell represents the data for an individual subject shown as a dose–response plot, ie, y-axis shows fasting glucose concentration in mmol/L and x-axis shows dose in mg.
Abbreviation: PKPD, pharmacokinetic/pharmacodynamic.

Figure 2 Plots of observed glucose concentrations (open circles), population model predictions (dotted line), and individual model predictions (solid line) for the steady state concentration (CPss) fasting glucose concentration PKPD model for glucose response to glibenclamide.

Notes: Each cell represents the data for an individual subject shown as a dose–response plot, ie, y-axis shows fasting glucose concentration in mmol/L and x-axis shows dose in mg.
Abbreviation: PKPD, pharmacokinetic/pharmacodynamic.

Table 1 Population pharmacokinetic/pharmacodynamic parameters for Models 1 and 2: fasting blood glucose as the pharmacodynamic response

	Dose–fasting glucose model			Cpss–fasting glucose model
Parameter	Estimate	RSE (%)	BSV (%CV)	Estimate	RSE (%)	BSV (%CV)
E0 (mmol/L)	14.10	6.35	29.05	14.30	6.04	27.40
Emax	0.37	37.47	48.68	0.39	22.64	55.50
ED50 (mg)	4.56	77.19	0.01	Derived ED50 = 4.41a
EC50 (mg/L)				85.20	26.29	0.04
Residual variability
Variance (%CV)	0.02 (15%)			0.02 (14%)

Note:

a Derived ED₅₀ = EC₅₀ × Cl/f × 24, where EC₅₀ = 85.20 mg/L and drug clearance (CL/f)⁹ = 2.16 L/h.

Abbreviations: E₀, baseline glucose concentration; E_max, maximum inhibition of glucose concentration; EC₅₀, glibenclamide concentration producing 50% inhibition of glucose concentration; ED₅₀, glibenclamide dose producing 50% inhibition of glucose concentration; RSE, relative standard error of the estimate; BSV, between-subject variability; CV, coefficient of variation; Cpss, steady-state glibenclamide concentration.

Figure 3 Plots of observed glucose concentrations (open circles), population model predictions (dotted line), and individual model predictions (solid line) for the steady state concentration (Cpss)-mean glucose concentration PKPD model for glucose response to glibenclamide.

Notes: Each cell represents the data for an individual subject shown as a dose–response plot, ie, y-axis shows fasting glucose concentration in mmol/L and x-axis shows dose in mg.
Abbreviation: PKPD, pharmacokinetic/pharmacodynamic.

Table 2 Population pharmacokinetic/pharmacodynamic parameters for Models 3 and 4: mean blood glucose as the pharmacodynamic response

	Dose–mean glucose model			Cpss–mean glucose model
Parameter	Estimate	RSE (%)	BSV (%CV)	Estimate	RSE (%)	BSV (%CV)
E0 (mmol/L)	16.70	5.74	27.07	16.70	5.74	26.94
Emax	0.34	14.32	50.99	0.34	14.49	50.89
ED50 (mg)	1.85	40.49	120.42	Derived ED50 = 1.87a
EC50 (mg/L)	–	–	–	36.00	42.78	108.17
Residual variability	–	–	–	–	–	–
Variance (%CV)	0.008 (8.75%)	–	–	0.008 (8.92%)	–	–

Note:

a Derived ED₅₀ = EC₅₀ × Cl/f × 24, where EC₅₀ = 36.00 mg/L and drug clearance (CL/f)⁹ = 2.16 L/h.

Abbreviations: E₀, baseline glucose concentration; E_max, maximum inhibition of glucose concentration; EC₅₀, glibenclamide concentration producing 50% inhibition of glucose concentration; ED₅₀, glibenclamide dose producing 50% inhibition of glucose concentration; RSE, relative standard error of the estimate; BSV, between-subject variability; CV, coefficient of variation; Cpss, steady-state glibenclamide concentration.

Figure 4 Plots of observed glucose concentrations (open circles), population model predictions (dotted line), and individual model predictions (solid line) for the Cpss–full glucose profile PKPD model.

Notes: Each row represents the data for an individual subject and each column represents a different dose level, with placebo on the extreme left and increasing doses of 2.5, 5, 10, and 20 mg in the subsequent columns.
Abbreviations: PKPD, pharmacokinetic/pharmacodynamic; Cpss, steady-state glibenclamide concentration.

Table 3 Population pharmacokinetic/pharmacodynamic parameters for the Models 5 and 6: full glucose profile as the pharmacodynamic response

	Dose–full glucose profile model			Cpss–full glucose profile model
Parameter	Estimate	RSE (%)	BSV (%CV)	Estimate	RSE (%)	BSV (%CV)
A0 (mmol/L)	15.90	4.71	28.71	15.40	5.40	32.71
A1	0.95	17.44	120.83	0.97	16.36	7.05
B1	1.45	36.34	120.83	1.45	34.21	7.05
A2	–1.95	–14.26	120.83	–1.86	–15.38	7.05
B2	2.63	8.75	120.83	2.57	8.05	7.05
Emax	0.34	14.97	5.75	0.31	9.20	45.39
ED50 (mg)	2.21	29.46	15.13	Derived ED50 = 2.26a
EC50 (mg/L)	–	–	–	43.60	21.06	220.91
Residual variability	–	–	–	–	–	–
Variance (%CV)	0.02 (13%)	–	–	0.02 (13%)	–	–

Note:

a Derived ED₅₀ = EC₅₀ × Cl/f × 24 where EC₅₀ = 43.60 mg/L and drug clearance (CL/f)⁹ = 2.16 L/h.

Abbreviations: A₀, baseline glucose concentration; A₁, B₁, A₂, B₂, coefficients of the harmonic function; E_max, maximum inhibition of glucose concentration; ED₅₀, glibenclamide dose producing 50% inhibition of glucose concentration; EC₅₀, glibenclamide concentration producing 50% inhibition of glucose concentration; RSE, relative standard error of the estimate; BSV, between-subject variability; CV, coefficient of variation; Cpss, steady-state glibenclamide concentration.

RambiritchVMaharajBNaidooPPillaiGPopulation pharmacokinetic modeling of glibenclamide in South African type 2 diabetic subjectsClin Pharmacol20168839227471411

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