Population Pharmacokinetics and Model-Based Dose Optimization of Vancomycin in Sudanese Adult Patients with Renal Impairment

Figures & data

Table 1 Summary of Patient Characteristics

Characteristics	Data	Range
Number of observations (Trough/Peak)	194 (129/65)	–
Trough concentrations, Median (IQR) (mg/l)	16.22 (11.1–26.53)	4.41–53
Peak concentrations, Median (IQR) (mg/l)	29.55 (22.38–37.36)	11.5–62.5
Number of subjects	99	–
Sex (Male/Female)	66/33	–
Age, Median (IQR) (Year)	65 (50–75)	18–90
Serum creatinine, Median (IQR) (mg/dl)	1.2 (0.7–2.5)	0.2–9.5
Serum albumin, Median (IQR) (g/dl)	2.5 (2.1–2.9)	1.4–4.1
Blood urea, Median (IQR) (mg/dl)	52 (26.1–89)	5–215
Creatinine clearance, Median (IQR) (mL/min)	12.7 (5.52–25.78)	1.4–107.5

Abbreviation: IQR, interquartile range.

Table 2 Summary of the Model Development Process

Model	Model Description	OFV	ΔOFV	P value
Forward Inclusion
1	Base Model	1411.35
2	Add logSCr on CL in Model 1	1367.62	−43.73	<0.05
3	Add logCLcr on CL in Model 1	1361.66	−49.69	< 0.05
4	Add Age in CL in Model 1	1394.45	−16.9	< 0.05
5	Add Blood Urea Nitrogen in CL in Model 1	1382.51	−28.84	< 0.05
6	Add Albumin in V in Model 1	1410.49	−0.86	> 0.05
7	Add Albumin in CL in Model 1	1411.05	−0.3	> 0.05
8	Add Age on CL in Model 3	1361.6	− 0.06	> 0.05
9	Add Blood Urea Nitrogen on CL in model 3	1361.28	−0.34	> 0.05
10	Add Albumin in V in model 3	1360.59	−1.07	> 0.05
Backward elimination
11	Remove CLcr on CL in Model 3	1411.601	49.9	> 0.01

Abbreviations: logSCr, log serum creatinine; CL, clearance (L/h); V, volume of distribution (L); OFV, objective function; ΔOFV, increase/decrease in OFV.

Table 3 Population Pharmacokinetic Parameter Estimate from Final Model and Bootstrap Validation

	VALUE	Monolix		Bootstrap
		S.E.	R.S.E. (%)	Median	2.5th	97.5th
	Fixed Effects
V_pop (L)	65	6.12	9.41	66.78	62.49	71.18
CL_pop (L/h)	2.02	0.13	6.40	2.004	1.92	2.08
beta_CL_logtCLcr	0.49	0.064	13	0.488	0.443	0.541
Standard Deviation of the Random Effects
omega_V	0.39	0.081	19.3	0.42	0.35	0.49
omega_Cl	0.46	0.061	12.5	0.45	0.41	0.49
Standard Deviation of the Proportional Error
b	0.28	0.023	8.26	0.28	0.26	0.29

Notes: V_pop and CL_pop; Typical value estimates of V and CL respectively, omega_V and omega_Cl: standard deviation of random effects of V and CL respectively, beta_CL_logtCLcr; fixed effect of CLcr on CL, b; standard deviation of proportional error model. , .

Figure 1 Simulated individual vancomycin clearance versus creatinine clearance.

Figure 2 Individual and conditional weighted residuals versus time after the last dose (TAD) for the final model.

Notes: (A) Individual weight residual error (IWRES) vs time after first dose. (B) Conditional weight residual error (CWRES) vs time after first dose.

Figure 3 Normalized prediction distribution error (NPDE) plots of the observed concentrations and the final model (mean, −0.04612 [P >0.05]; variance, 0.8686326 [P > 0.05]).

Notes: (A) Histogram of the distribution of normalized prediction distribution error (NPDE) plots of the observed concentrations. (B) Histogram of the distribution of normalized prediction distribution error (NPDE) plots of the individual weighted predicted concentrations (IWRES) of the final model.

Figure 4 Plot of the individual and population predictions versus observations for the final model.

Notes: (A) Observations vs individual prediction (OBS-PRED). (B) Observations vs population predicted concentrations (OBS-IPRED).

Figure 5 Visual predictive check (VPC) for vancomycin concentration versus time after first record for the final model. The dashed and solid black lines represent the 5th, 50th, and 95th percentiles of the observed data. The shaded regions represent the 95% confidence intervals around the 5th, 50th, and 95th percentiles of the simulated data.

Figure 6 Bootstrap result for final model.

Notes: (A) V_pop: Typical value estimates of volume of distribution. (B) Cl_pop; Typical value estimates of clearance. (C) beta_Cl_logtCLcr; Fixed effect of creatinine clearance on CL. (D) omega_V: Standard deviation of random effects of volume of distribution. (E) omega_Cl: Standard deviation of random effects clearance. (F) b: Standard deviation of proportional error model.

Table 4 Optimal Maintenance Dose Based on Simulations with the Final Model

CLcr Group Ranges (mL/min)	Optimal Maintenance Dose (mg/24 h) ^a	AUC24–48 (mg·h/L) ^b	PTA for AUC24–48 > 400 (mg·h/L) ^c	400 < AUC24–48 < 600 (mg·h/L) ^c	PTA for AUC24–48 > 600 (mg·h/L) ^c	Vd Median [95% Interval] L ^d	CL Median [95% Interval] L/h ^d
50–59	1650	491.78 [263.77–864.72]	0.72	0.44	0.28	66.14 [49.83–87.06]	4.28 [3.11–5.91
40–49	1300	492.39 [267.29–860.49]	0.73	0.44	0.28	65.64 [49.49–86.25]	3.88 [2.81–5.35
30–39	1000	503.46 [279.27–863.8]	0.74	0.45	0.3	65.97 [49.77–87.21]	3.42 [2.5–4.7
20–29	400	489.89 [275.18–842.12]	0.73	0.46	0.27	66.07 [50.11–87.05]	2.9 [2.09–4
10–19	200	455.62 [259.25–778.99]	0.66	0.46	0.2	65.28 [49.7–86.17]	2.22 [1.61–3.06

Notes: ^aAll vancomycin maintenance dosages were simulated after loading doses of 1800 and 1500 mg for the CLcr (20–59) and (10 −19) mL/min respectively. ^bAUC_24–48 corresponds to the AUC estimated during the second day of therapy with results reported as median (95% tolerance interval). ^cPTA are given as proportions. ^dPK parameters (volume of distribution and clearance) for the simulated individuals reported as median (95% tolerance interval).

Table 5 PK/PD Simulation for Probability of Target Attainment > 90%

CLcr Group Ranges (mL/min)	Optimal Maintenance Dose (mg/24 h)^a	AUC24–48 (mg.h/L)^b	PTA for AUC24–48 > 400 (mg.h/L)^c	PTA for AUC24–48 > 600 (mg.h/L)^c	Vd Median [95% Interval] L^d	CL Median [95% Interval] L/h^d
50–59	2650	578.07 [312.9–1012.21]	0.85	0.46	66.14 [49.83–87.06]	4.28 [3.11–5.91
40–49	2300	583.75 [320.18–1014.78]	0.86	0.47	65.64 [49.49–86.25]	3.88 [2.81–5.35
30–39	2000	601.18 [337.56–1026.61]	0.89	0.50	65.97 [49.77–87.21]	3.42 [2.5–4.7
20–29	1400	595.76 [339.32–1019.1]	0.88	0.49	66.07 [50.11–87.05]	2.9 [2.09–4
10–19	1200	574.12 [330.62–975.46]	0.87	0.45	65.28 [49.7–86.17]	2.22 [1.61–3.06

Notes: ^aAll vancomycin maintenance dosages were simulated after loading doses of 1800 and 1500 mg for the CLcr (20–59) and (10 −19) mL/min respectively. ^bAUC_24–48 corresponds to the AUC estimated during the second day of therapy with results reported as median (95% tolerance interval). ^cPTA are given as proportions. ^dPK parameters (volume of distribution and clearance) for the simulated individuals reported as median (95% tolerance interval).