Population-Based Pharmacokinetics and Dose Optimization of Imipenem in Vietnamese Critically-Ill Patients

Figures & data

Table 1 Demographic Characteristics

Characteristic	Total (Mean±SD)
Gender
Male	18
Female	6
Age (years)	57.5±19.9
Actual body weight (kg)	51.3±8.6
Creatinine clearance (mL/min)	68.3±39.6
Serum albumin (g/dL)	32.7±4.67
Dose regimen
0.5g q8h	19 (79.2%)
0.5g q6h	2 (8.3%)
1g q8h	3 (12.5%)
Mechanical ventilation	14 (58.3%)
Unit
ICU	20 (83.3%)
General medicine	4 (16.7%)
Vasopressor	7 (29.2%)

Abbreviations: ICU, intensive care unit; SD, standard deviation.

Table 2 Parameter Estimates of Final Population Pharmacokinetic Model for Imipenem

Parameter	Final model		Bootstrap Result (N=1000)
	Estimate	RSE%	5th Percentile	Median	95th Percentile
Structural model
Cl (L/h) = Clpop x e^Beta_Clcr x Clcr
Clpop (L/h)	4.79	18.3	2.792	4.65	6.569
Beta_Clcr	0.00642	36.4	0.002	0.0065	0.012
Vc (L)	11.1	14.1	5.3	10.38	14.865
Q (L/h)	11.1	40.6	4.611	10.70	130.237
Vp (L)	8.82	23.3	5.063	14.37	32.259
Between-subject variability (CV,%)
IIV_CL	38.7	18.2	16.8	35.3	30.7
IIV_Vc	56.3	19	20.8	52.1	81.3
IIV_Q	110.0	35.9	24.9	97.3	250.2
IIV_Vp	69.4	34.3	18.2	64.2	200.5
Residual variability
Additive error (mg/L)	0.445	13.1	0.326	0.436	0.544
Proportional error (%)	22.1	14.3	15.8	21.9	27.4

Abbreviations: Cl, clearance; Clpop, typical population estimate of clearance; Beta_Clcr, coefficient of clearance creatinine on the imipenem’s clearance; Clcr, creatinine clearance; Vc, volume of distribution of central compartment; Vp, volume of distribution of peripheral compartment; Q, inter-compartemental clearance; IIV_CL, Inter-individual variability on clearance; IIV_Vc, Inter-individual variability on volume of distribution of central compartment; IIV_Vp, Inter-individual variability on volume of distribution of peripheral compartment; IIV_Q, Inter-individual variability on intercompartemental clearance; CV, coefficient of variation; RSE, relative standard error.

Figure 1 GOF plots of final models showing observed versus population predicted concentration (A), observed vs individual predicted concentration (B).

Figure 2 Scatter plot of the residuals: Individual weighted residuals (IWRES), seen on the left-hand side of the figure, versus time after dose (top) and concentration (bottom); Normalized Prediction Distribution Error (NDPE, 1000 replicates), seen on the right-hand side of the figure, versus time after dose (top) and concentration (bottom).

Figure 3 Visual Predictive Checks of observed imipenem concentrations (solid line) along with 10th, 50th and 90th percentiles overlaid on median (dashed line) and 90% prediction intervals (shaded region) of simulated concentrations generated from final model (1000 replicates).

Figure 4 Probability of target attainment (PTA) of various imipenem dose regimens with a target of 40% (upper panels) and 100%T>MIC (lower panels), stratified based on patient renal function: <30, 30–60, 60–90, and >90 mL/min.