Article Figures & Data
Figures
- FIG 1
Visual predictive check based on the final model. Red circles, the observed concentrations in the current study; red solid line, the median of the observations; red dashed lines, 95th and 5th outer percentiles of the observations. The shaded area is derived from simulations from the final model, with the central dark gray area representing a 95% confidence interval for the median and the light gray areas representing the 95% confidence intervals for the 95th and 5th outer percentiles of the simulations.
- FIG 2
Predictions from the model for nine dosing regimens with a total administration of 16 g (A), 12 g (B), or 8 g (C) over 24 h for the median (left) and highest (right) creatinine clearances. Horizontal dashed lines, an MIC of 16 mg/liter. Continuous infusion was initiated with a loading dose of 4 g. IA, intermittent administration; EI, extended infusion; CI, continuous infusion.
- FIG 3
Probability of target attainment (PTA) for each of the nine regimens using the final model and a distribution of creatinine clearance values. The graphs indicate the total administration of 16 g (A), 12 g (B), or 8 g (C) as intermittent administration (IA), extended infusion (EI), or continuous infusion (CI). Dashed lines, 90% of the simulated patients reached the specified target; fTMIC, the percentage of the dosing interval that the free drug concentration is maintained above the MIC.
- FIG 4
Probability of target attainment (PTA) for intermittent administration (IA) at 4 g q8h using the final model and a distribution of creatinine clearance values split into three empirical categories. Dashed lines, PTA of 90%; fTMIC, the percentage of the dosing interval that the free drug concentration is maintained above the MIC.
Tables
- TABLE 1
Patient characteristicsa
Characteristic Values Median (IQR) age (yr) 57 (33, 76) No. (%) of subjects who were: Male 12 (55) Female 10 (45) Median (IQR) body wt (kg) 76 (64, 82) Median (IQR) plasma creatinine concn (μmol/liter) 97 (66, 132) Median (IQR) plasma albumin concn (g/liter) 28 (24, 31) eCLCR (ml/min) 83.9 (46, 152) ↵a Data are for 22 patients. IQR, interquartile range; eCLCR, estimated creatinine clearance, determined using the Cockcroft-Gault formula.
- TABLE 2
The final parameter estimates from the current analysisa
Parameter Parameter description Estimated value from final model % RSE (% SHR) CLother (liters/h) Nonrenal clearance 2.23 36 θeCLCR-COV eCLCR covariate effect 0.0757 12 VC (liters) Volume of distribution of central compartment 12.4 8.3 Q (liters/h) Compartmental clearance 3.54 3.0 VP (L) Volume of distribution of peripheral compartment 3.48 11 % CV for CL Variability in clearance 29.7 13 (1.8) % CV for ERR Proportional residual error 11.5 21 (7.4) ↵a Total clearance was parameterized according to the formula CLtotal,i = (CLother + θeCLCR-COV · eCLCR,i) · eηi, where CLtotal,i is the individual total clearance (in millimeters per minute), CLother is an estimated parameter describing nonrenal clearance (in liters per hour), θeCLCR-COV is the estimated covariate effect, eCLCR,i is the individual eCLCR (in millimeters per minute), and ηi is the deviation from the typical clearance in the individual. CV, coefficient of variation; CL, clearance; ERR, error; RSE, relative standard error; SHR, shrinkage.
- TABLE 3
Number of subjects included in the analysis that were predicted to achieve the two PK/PD targetsa
Regimen No. of subjects predicted to achieve the following fTMIC target/total no. of subjects evaluated (%) 50% 100% IA at 4 g q6h 19/22 (86) 9/22 (40) IA at 4 g q8h 15/22 (68) 4/22 (18) IA at 4 g q12h 9/22 (41) 2/22 (9) EI at 4 g q6h 22/22 (100) 14/22 (64) EI at 4 g q8h 21/22 (95) 7/22 (32) EI at 4 g q12h 14/22 (64) 2/22 (9) CI at 16 g 22/22 (100) 22/22 (100) CI at 12 g 22/22 (100) 22/22 (100) CI at 8 g 22/22 (100) 22/22 (100) ↵a PK/PD, pharmacokinetic/pharmacodynamic; fTMIC, percentage of the dosing interval that the free drug concentration is maintained above the MIC; IA, intermittent administration; EI, extended infusion; CI, continuous infusion.
- TABLE 4
PTA for each of the nine regimens for MICs of 16 mg/liter and the MIC value at which PTA is predicted to be 90%a
Regimen PTA (%) of the following for MIC of 16.0 mg/liter: MIC (μg/ml) for PTA of 90% for: 50% fTMIC 100% fTMIC 50% fTMIC 100% fTMIC IA at 4 g q6h 88.0 38.8 14.4 2.0 IA at 4 g q8h 70.2 18.3 7.0 0.5 IA at 4 g q12h 36.6 3.7 1.9 <0.125 EI at 4 g q6h 100 64.0 44.0 6.1 EI at 4 g q8h 96.2 31.8 22.3 1.6 EI at 4 g q12h 60.9 6.6 5.6 <0.125 CI at 16 g 100 100 44.5 44.5 CI at 12 g 100 100 33.7 33.5 CI at 8 g 98.4 98.4 22.2 22.2 ↵a IA, intermittent administration; EI, extended infusion; CI, continuous infusion; fTMIC, percentage of the dosing interval that the free drug concentration is maintained above the MIC; PTA, probability of target attainment.
