Dosing Evaluation of Ceftazidime–Avibactam in Intensive Care Unit Patients Based on Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Simulation
Abstract
:1. Introduction
2. Results
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. Pharmacokinetic–Pharmacodynamic (PK/PD) Modeling
- Pharmacokinetic model
- Pharmacodynamic model
- -
- Population 1 (P₁) with active microbial growth and an initial inoculum of 10⁶ CFU/mL.
- -
- Population 2 (P₂) in the resting phase with an initial inoculum of 1/10⁷ CFU/mL.
- Model validation
- Monte Carlo simulations
4.3. PK/PD Analysis
- -
- Time during the serum drug concentration remains above the minimum inhibitory concentration (MIC) (T > MIC)
- -
- Ratio of the trough serum concentration to the MIC (Cmin/MIC).
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Mean Value Predicted | Mean Value Observed | AFE | |
---|---|---|---|
a (mg/L) | 95.9 | 90.1 [7] | 1.06 |
b (mg/L) | 67.8 | 53.8 [11] | 1.27 |
c (mg/L) | 15.9 | 14.5 [7] | 1.10 |
Bacterial density d (LogCFU/mL) | 9.23 | 9.1 [12] | 1.01 |
Bacterial density e (LogCFU/mL) | 8.78 | 8.0 [12] | 1.10 |
Bacterial density f (LogCFU/mL) | 6.57 | 4.7 [12] | 1.40 |
Population | Clcr (mL/min) | Ceftazidime PK Parameters | Avibactam PK Parameters | ||||
---|---|---|---|---|---|---|---|
Cl (L/h) [CV (%)] | V (L) [CV (%)] | t ½ (h) [CV (%)] | Cl (L/h) [CV (%)] | V (L) [CV (%)] | t ½ (h) [CV (%)] | ||
Control | 100 | 6.08 [35.2] | 15.7 [40.8] | 1.99 [53.3] | 12.2 [26.5] | 20.2 [53.6] | 1.22 [59.0] |
60 | 3.82 [34.5] | 3.17 [53.0] | 7.57 [26.6] | 1.96 [59.2] | |||
40 | 2.26 [40.3] | 4.55 [52.7] | 5.19 [26.8] | 2.87 [59.2] | |||
20 | 1.59 [34.0] | 7.61 [52.7] | 2.99 [28.1] | 5.00 [59.8] | |||
10 | 0.93 [35.5] | 13.1 [54.2] | 1.65 [32.1] | 9.24 [62.6] | |||
3 | 0.48 [47.9] | 27.7 [65.3] | 0.73 [53.4] | 24.4 [80.1] | |||
ICU | 100 | 5.44 [31.8] | 34.5 [33.9] | 4.84 [47.7] | 10.9 [28.0] | 51.0 [31.7] | 3.49 [41.5] |
60 | 3.73 [31.4] | 7.04 [47.3] | 6.90 [27.7] | 5.49 [41.02] | |||
40 | 2.86 [31.8] | 9.23 [47.7] | 4.86 [28.0] | 7.80 [41.3] | |||
20 | 2.05 [35.1] | 13.1 [49.3] | 2.99 [32.8] | 12.8 [42] | |||
10 | 1.56 [41.7] | 17.9 [53.4] | 1.85 [36.2] | 21.4 [45.3] | |||
3 | 1.22 [50.8] | 24.6 [61.7] | 1.06 [55.7] | 43.2 [60.5] |
Dosage Regimen | Population | Clcr (mL/min) | Dosage Regimen ((CAZg/AVIg)/h) | Bacterial Density Change a | T > MIC | Cmin/MIC |
---|---|---|---|---|---|---|
(%) (5/95%) | (%) (5/95%) | Mean (5/95%) | ||||
Summary of Product Characteristics | Control | 100 | (2.0/0.5)/8 | −63.7 (−99.3/24.5) | 95.4 (62.9/100) | 0.81 (0.00/4.75) |
60 | (2.0/0.5)/8 | −78.3 (−99.3/−1.50) | 100 (75.9/100) | 4.42 (0.03/15.4) | ||
40 | (1.0/0.25)/8 | −76.0 (−99.3/3.83) | 100 (74.5/100) | 4.25 (0.12/12.9) | ||
20 | (0.75/0.19)/12 | −69.5 (−99.3/16.0) | 100 (66.8/100) | 3.40 (0.06/10.7) | ||
10 | (0.75/0.19)/24 | −51.2 (−99.0/38.5) | 100 (53.1/100) | 2.04 (0.01/7.62) | ||
3 | (0.75/0.19)/48 | −44.7 (−98.5/44.0) | 100 (42.5/100) | 2.08 (0.00/9.13) | ||
ICU | 100 | (2.0/0.5)/8 | −77.5 (−99.3/0.67) | 100 (77.6/100) | 4.47 (0.20/12.7) | |
60 | (2.0/0.5)/8 | −84.8 (−99.3/−19) | 100 (100/100) | 9.76 (1.70/21.6) | ||
40 | (1.0/0.25)/8 | −80.0 (−99.3/−5.33) | 100 (98.4/100) | 6.43 (1.06/14.3) | ||
20 | (0.75/0.19)/12 | −65.7 (−99.3/25.5) | 100 (64.6/100) | 3.50 (0.00/19.0) | ||
10 | (0.75/0.19)/24 | −30.2 (−96.83/57.83) | 100 (38.2/100) | 1.18 (0.00/19.0) | ||
3 | (0.75/0.19)/48 | 13.0 (−78.8/70.5) | 59.6 (23.5/100) | 0.35 (0.00/19.0) | ||
Suggested | Control | 10 | (0.75/0.19)/12 | −83.7 (−99.3/−15.3) | 100 (100/100) | 10.1 (1.88/22.0) |
3 | (0.75/0.19)/24 | −80.8 (−99.3/−6.5) | 100 (75.0/100) | 9.37 (0.53/25.7) | ||
ICU | 10 | (0.75/0.19)/12 | −79.5 (−99.3/−0.83) | 100 (94.1/100) | 6.00 (0.97/13.2) | |
3 | (0.75/0.19)/24 | −56.5 (−99.2/37) | 100 (44.8/100) | 2.63 (0.01/9.35) |
Clcr (mL/min) | CAZ Dose (g) | AVI Dose (g) | Interval (h) | |
---|---|---|---|---|
SmPC | 100 | 2.0 | 0.5 | 8 |
60 | 2.0 | 0.5 | 8 | |
40 | 1.0 | 0.25 | 8 | |
20 | 0.75 | 0.19 | 12 | |
10 | 0.75 | 0.19 | 24 | |
3 | 0.75 | 0.19 | 48 |
Parameter | Control Population | ICU Patient Population | ||
---|---|---|---|---|
CAZ | AVI | CAZ | AVI | |
Vd (L/kg) | 0.21 (38.1) | 0.27 (51.8) | 0.46 (30.4) | 0.68 (27.9) |
Cli (L/h) | 0.39 (55.6) | 0.53 (65.6) | 1.15 (54.8) | 0.89 (65.2) |
CLs | 0.06 (36.9) | 0.12 (27.3) | 0.04 (37.2) | 0.10 (30.0) |
Parameter | Description | Value [CV (%)] | Units |
---|---|---|---|
Nmax | Maximum load capacity achievable in the system. | 9.89 [2.06] | CFU/mL |
kgrowth,1 | Bacterial growth associated with the log10 of the active population P1. | 0.346 [20.9] | h−1 |
kgrowth,2 | Bacterial growth rate constant associated with the log10 of the active population P₂. | (1/107) × Kgrowth,1 | h−1 |
Emax | Maximum kill rate constant due to CAZ. | 0.240 [16.0] | h−1 |
A | First coefficient of the biexponential function to characterize the EC50 of CAZ. | 52.3 [17.2] | mg/L |
B | Second coefficient of the biexponential function to characterize the EC50 of CAZ. | 12.6 [26.0] | mg/L |
α | Exponential constant associated with parameter A that describes the relationship between the concentration of AVI and the potency of CAZ. | 2.38 [119] | L/mg |
β | Exponential constant associated with parameter B that describes the relationship between the concentration of AVI and the potency of CAZ. | 9.67 E2 [7.01] | L/mg |
ϒ | Hill coefficient characterizing the steepness of the slope of the sigmoidal Emax curve associated with the increase in potency of CAZ by AVI. | 2.60 [34.23] | - |
δ1 | Exponential constant of the delay function to retard the active population, P₁. | 4.23 E2 (fixed) | h−1 |
δ2 | Exponential constant of the delay function to slow the initial death of the active population, P₁. | 0.213 [17.46] | h−1 |
k1–2 | Rate constant for the conversion of bacterial cells from active to resting states. | 5.0 E3 (fixed) | CFU/mL/h |
Degmax | Maximum degradation rate constant of CAZ. | 7.71 E2 [51.9] | h−1 |
Km | CFU density that yielded 50% of the maximum degradation rate. | 8.5 (fixed) | CFU/mL |
Hill coefficient that characterizes the slope of the sigmoid Emax model for CAZ degradation. | 1.46 [82.2] | - | |
IC₅₀ | AVI concentration that yielded a 50% decrease in the degradation rate. | 1.96 [58.2] | mg/L |
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Zazo, H.; Aguazul, Y.; Lanao, J.M. Dosing Evaluation of Ceftazidime–Avibactam in Intensive Care Unit Patients Based on Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Simulation. Antibiotics 2024, 13, 861. https://doi.org/10.3390/antibiotics13090861
Zazo H, Aguazul Y, Lanao JM. Dosing Evaluation of Ceftazidime–Avibactam in Intensive Care Unit Patients Based on Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Simulation. Antibiotics. 2024; 13(9):861. https://doi.org/10.3390/antibiotics13090861
Chicago/Turabian StyleZazo, Hinojal, Yuridia Aguazul, and José M. Lanao. 2024. "Dosing Evaluation of Ceftazidime–Avibactam in Intensive Care Unit Patients Based on Pharmacokinetic/Pharmacodynamic (PK/PD) Modeling and Simulation" Antibiotics 13, no. 9: 861. https://doi.org/10.3390/antibiotics13090861