PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Pharmacokinetic Analysis Software
2.3. PBPK Modeling and Simulation
3. Results
3.1. Influence of Dose Regimens and Biological Sex
3.2. Influence of Total Body Weight
3.3. Influence of Renal Function
3.4. Effect of Renal Function on the Accumulation of Drugs in Plasma over Time
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Amikacin | Gentamicin | Tobramycin | Vancomycin | |
---|---|---|---|---|
nt (nsex) | 8 (F: 1; M: 7) | 22 (F: 8; M: 14) | 5 (F: 4; M: 1) | 47 (F: 21; M: 26) |
Age (years) | 14–87 (avg 57) | 7–88 (avg 58) | 13–19 (avg 15) | 19–93 (avg 63) |
Weight (kg) | 50.0–92.5 (avg 66.0) | 15.5–85.0 (avg 66.0) | 25.8–44.5 (avg 33.0) | 29.0–140. (avg 69.0) |
Height (cm) | 163–180 (avg 169) | 108–185 (avg 165) | 130–158 (avg 146) | 147–185 (avg 163) |
Cmin (mg/L) | 0.30–16.40 (avg 3.70) (ref 1–8) | 0.20–4.80 (avg 1.05) (ref 0.5–2) | 0.06–0.23 (avg 0.17) (ref 0.5–2; <1 CF) | 4.50–45.60 (avg 16.34) (ref 15–20) |
Cmax (mg/L) | 19.70–87.80 (avg 38.97) (ref 20–30) | 2.90–19.50 (avg 9.22) (ref 5–10) | 16.32–36.12 (avg 27.05) (ref 5–10; 20–30 CF) | 11.20–60.10 (avg 25.99) (ref < 40) |
[Cr] (mg/dL) | 0.47–1.58 (avg 0.93) | 0.29–1.89 (avg 0.83) | 0.35–0.64 (avg 0.49) | 0.27–4.78 (avg 1.00) |
CL (L/h) * | 1.40–11.30 (avg 6.07) | 1.67–15.89 (avg 5.94) | 3.87–8.77 (avg 6.01) | 0.59–18.80 (avg 5.79) |
Amikacin | Gentamicin | Tobramycin | Vancomycin | |
---|---|---|---|---|
Molecular weight | 585.61 | 477.61 | 467.52 | 1449.28 |
logP | −5 1 | −1.79 1; −3.1 2 | −4.8 1; −5.8 2 | 2.48 1; −3.1 2 |
pKa | 8.1 2 | 12.55; 10.18 2 | 12.54; 9.83 2 | 2.99; 9.93 2 |
Solubility | 166.49 g/L, pH = 11.73 1; 50 g/L 2 | 56.54 g/L, pH = 11.51 1; 12.6 g/L 2 | 59.47 g/L, pH = 11.34 1; freely soluble 2 | 0.26 g/L, pH = 8.17 1; 0.225 g/L 2 |
Diffusion Coefficient | 0.53 cm2/s × 105 1 | 0.56 cm2/s × 105 1 | 0.6 cm2/s × 105 1 | 0.32 cm2/s × 105 1 |
Drug particle density | 1.2 g/mL | 1.2 g/mL | 1.2 g/mL | 1.2 g/mL |
Mean particle radius | 25 | 25 | 25 | 25 |
Peff | 0.0202 cm/s × 10−4 1 | 0.0891 cm/s × 10−4 1 | 0.0368 cm/s × 10−4 1 | 0.0747 cm/s × 10−4 1 |
Fup | 98.75% 1; >90% 2 | 85.4% 1; >70% 2 | 100% 1; >70% 2 | 21.36% 1; ~50% 2 |
Blood/plasma ratio | 1.23 1 | 1.11 1 | 1.31 1 | 0.68 1 |
T1/2 | 2–3 h | 2–3 h | 2–3 h | ~6 h (4–11 h) |
Vc | 0.24 1; ~0.34 L/kg 2 | 0.38 1; 0.2–0.3 L/kg | 0.3 1; 0.2–0.3 L/kg | 0.4–1 L/kg |
Clearance | 6.00 L/h | 3.42 L/h | 8.48 L/h | 4.03 L/h |
Typical dosing for susceptible infections | 7.5 mg/kg q12h 15 mg/kg q24h | 1 mg/kg q8h | 1 mg/kg q8h | 1000 mg q12h |
Common dosing in CHUP | Variable: 400–800 mg q24h or q48h | 120 mg q8h 200 mg q24h 70 mg q12h | 70 mg q8h 420 mg q24h | 1 g q12h 1 g q24h |
Drug & Posology | Fa (%) 1 | FDp (%) 2 | F (%) 3 | Cmax (mg/L) 4 | Tmax (h) 5 | AUC0-inf (µg∙h/mL) 6 | AUC0-t (µg∙h/mL) 7 | Cmax liver (mg/L) 8 |
---|---|---|---|---|---|---|---|---|
Amikacin | ||||||||
400 mg q24h | 99.980 | 99.964 | 99.964 | 5.981 | 48.5 | 197.570 | 94.836 | 64.761 |
800 mg q24h | 99.980 | 99.964 | 99.964 | 11.962 | 48.5 | 395.150 | 189.670 | 129.520 |
800 mg q24h female | 99.978 | 99.960 | 99.960 | 11.790 | 48.5 | 395.060 | 209.520 | 128.610 |
Gentamicin | ||||||||
70 mg q12h | 99.859 | 99.834 | 99.834 | 1.446 | 60.5 | 68.971 | 32.731 | 14.831 |
120 mg q8h | 99.864 | 99.838 | 99.838 | 2.981 | 64.5 | 163.850 | 81.287 | 31.975 |
200 mg q24h | 99.845 | 99.822 | 99.822 | 3.304 | 48.5 | 100.650 | 51.345 | 31.876 |
200 mg q24h female | 99.829 | 99.806 | 99.806 | 3.246 | 48.5 | 100.630 | 56.321 | 31.524 |
Tobramycin | ||||||||
250 mg q24h | 99.971 | 99.971 | 99.971 | 5.702 | 48.5 | 124.780 | 78.230 | 62.346 |
500 mg q24h | 99.971 | 99.971 | 99.971 | 11.403 | 48.5 | 249.570 | 156.460 | 124.690 |
420 mg q24h | 99.971 | 99.971 | 99.971 | 9.579 | 48.5 | 209.640 | 131.430 | 104.740 |
420 mg q24h female | 99.969 | 99.969 | 99.969 | 9.460 | 48.5 | 209.640 | 139.840 | 104.770 |
Vancomycin | ||||||||
500 mg q12h | 99.929 | 99.921 | 99.921 | 15.632 | 61.0 | 517.990 | 452.870 | 30.871 |
1000 mg q24h | 99.926 | 99.921 | 99.921 | 25.547 | 49.0 | 518.000 | 477.990 | 50.086 |
1000 mg q12h | 99.929 | 99.921 | 99.921 | 31.263 | 61.0 | 1036.000 | 905.740 | 61.742 |
1000 mg q12h female | 99.930 | 99.921 | 99.921 | 29.202 | 61.0 | 1036.000 | 901.460 | 57.773 |
Drug & Posology | Fa (%) 1 | FDp (%) 2 | F (%) 3 | Cmax (mg/L) 4 | Tmax (h) 5 | AUC0-inf (µg∙h/mL) 6 | AUC0-t (µg∙h/mL) 7 | Cmax liver (mg/L) 8 |
---|---|---|---|---|---|---|---|---|
Amikacin | ||||||||
800 mg q24h BW avg (66.0 kg) | 99.980 | 99.964 | 99.964 | 11.962 | 48.5 | 395.150 | 189.670 | 129.520 |
800 mg q24h BW min (50.0 kg) | 99.981 | 99.965 | 99.965 | 14.813 | 48.5 | 395.250 | 223.520 | 161.780 |
800 mg q24h BW max (92.5 kg) | 99.982 | 99.966 | 99.966 | 9.161 | 48.5 | 394.940 | 151.390 | 97.834 |
Gentamicin | ||||||||
200 mg q24h BW avg (66.0 kg) | 99.845 | 99.822 | 99.822 | 3.304 | 48.5 | 100.650 | 51.345 | 31.876 |
200 mg q24h BW min (15.5 kg) | 99.910 | 99.905 | 99.905 | 9.555 | 48.5 | 100.890 | 90.418 | 97.446 |
200 mg q24h BW max (85.0 kg) | 99.680 | 99.656 | 99.656 | 9.546 | 48.5 | 100.630 | 90.200 | 97.126 |
Tobramycin | ||||||||
420 mg q24h BW avg (33.0 kg) | 99.971 | 99.971 | 99.971 | 9.579 | 48.5 | 209.640 | 131.430 | 104.740 |
420 mg q24h BW min (25.8 kg) | 99.973 | 99.973 | 99.973 | 11.479 | 48.5 | 209.660 | 147.220 | 127.010 |
420 mg q24h BW max (44.5 kg) | 99.970 | 99.970 | 99.970 | 7.646 | 48.5 | 209.600 | 111.740 | 82.333 |
Vancomycin | ||||||||
1000 mg q12h BW avg (69.0 kg) | 99.929 | 99.921 | 99.921 | 31.263 | 61.0 | 1036.000 | 905.740 | 61.742 |
1000 mg q12h BW min (29.0 kg) | 99.956 | 99.954 | 99.954 | 48.459 | 61.0 | 1036.300 | 1005.000 | 95.749 |
1000 mg q12h BW max (140.0 kg) | 99.936 | 99.926 | 99.926 | 22.535 | 61.0 | 1035.800 | 736.330 | 44.587 |
Drug & Posology | Fa (%) 1 | FDp (%) 2 | F (%) 3 | Cmax (mg/L) 4 | Tmax (h) 5 | AUC0-inf (µg∙h/mL) 6 | AUC0-t (µg∙h/mL) 7 | Cmax liver (mg/L) 8 |
---|---|---|---|---|---|---|---|---|
Amikacin | ||||||||
800 mg q24h CL avg (6.068 L/h) | 99.980 | 99.964 | 99.964 | 11.962 | 48.5 | 395.150 | 189.670 | 129.520 |
800 mg q24h CL min (1.401 L/h) | 99.974 | 99.950 | 99.950 | 13.293 | 48.5 | 1705.900 | 258.260 | 147.360 |
800 mg q24h CL max (11.298 L/h) | 99.985 | 99.973 | 99.973 | 11.015 | 48.5 | 212.320 | 142.930 | 117.190 |
Gentamicin | ||||||||
200 mg q24h CL avg (5.941 L/h) | 99.845 | 99.822 | 99.822 | 3.304 | 48.5 | 100.650 | 51.345 | 31.876 |
200 mg q24h CL min (1.667 L/h) | 99.789 | 99.751 | 99.751 | 3.667 | 48.5 | 355.600 | 69.999 | 36.212 |
200 mg q24h CL max (15.887 L/h) | 99.908 | 99.899 | 99.899 | 2.860 | 48.5 | 37.744 | 30.152 | 26.809 |
Tobramycin | ||||||||
420 mg q24h CL avg (6.007 L/h) | 99.971 | 99.971 | 99.971 | 9.579 | 48.5 | 209.640 | 131.430 | 104.740 |
420 mg q24h CL min (3.868 L/h) | 99.965 | 99.965 | 99.965 | 10.149 | 48.5 | 325.460 | 158.850 | 111.740 |
420 mg q24h CL max (8.771 L/h) | 99.977 | 99.977 | 99.977 | 9.032 | 48.5 | 143.600 | 106.330 | 98.209 |
Vancomycin | ||||||||
1000 mg q12h CL avg (5.787 L/h) | 99.929 | 99.921 | 99.921 | 31.263 | 61.0 | 1036.000 | 905.740 | 61.742 |
1000 mg q12h CL min (0.590 L/h) | 99.789 | 99.743 | 99.743 | 73.192 | 61.0 | 10090.000 | 2659.400 | 146.400 |
1000 mg q12h CL max (18.796 L/h) | 99.976 | 99.974 | 99.974 | 19.356 | 61.0 | 319.140 | 313.790 | 38.136 |
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Ferreira, A.; Martins, H.; Oliveira, J.C.; Lapa, R.; Vale, N. PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice. Life 2021, 11, 1130. https://doi.org/10.3390/life11111130
Ferreira A, Martins H, Oliveira JC, Lapa R, Vale N. PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice. Life. 2021; 11(11):1130. https://doi.org/10.3390/life11111130
Chicago/Turabian StyleFerreira, Abigail, Helena Martins, José Carlos Oliveira, Rui Lapa, and Nuno Vale. 2021. "PBPK Modeling and Simulation of Antibiotics Amikacin, Gentamicin, Tobramycin, and Vancomycin Used in Hospital Practice" Life 11, no. 11: 1130. https://doi.org/10.3390/life11111130