Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. Intervention
2.3. Blood and Microdialysate Samples
2.4. Microdialysis
2.5. Study Visits and Data Collection
2.6. Drug Analysis
2.7. Study Endpoints
2.8. Pharmacokinetic and Statistical Analysis
3. Results
3.1. Participants
3.2. Primary (ISF) and Secondary Study Endpoint (Plasma): Correlation of AUC0–8 with Weight
3.3. Analysis of ISF and Plasma Data as Functions of Time
3.4. PK Parameters in ISF and Plasma and Statistical Analysis
3.5. PK Relations to MIC Values for Susceptible Bacteria
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Obese (n = 15) | Non-Obese (n = 15) | |
---|---|---|
Number of females (n (%)) | 13 (87%) | 13 (87%) |
Age (years) | 50.3 ± 9.5 | 49.5 ± 10.0 |
Weight (kg) | 134.3 ± 34.3 | 67.9 ± 8.8 |
Height (m) | 1.66 ± 0.07 | 1.68 ± 0.07 |
BMI (kg/m2) | 48.7 ± 11.2 | 23.9 ± 2.1 |
Creatinine (µmol/L) | 86.4 ± 27.2 | 75.3 ± 18.9 |
Type of surgery (n (%)) | ||
laparoscopic | 15 (100%) | 3 (20%) |
open | 0 (0%) | 12 (80%) |
ASA classification (n (%)) | ||
I | 1 | 2 |
II | 4 | 11 |
III | 10 | 2 |
All Patients (n = 30) | Pearson’s Correlation Coefficient with Weight | Obese (n = 15) | Non-Obese (n = 15) | p-Value | |
---|---|---|---|---|---|
Cmax (mg/L) | |||||
ISF | 5.5 [3.8, 8.5] | −0.70 (−0.85 to −0.45) | 3.8 [3.2, 5.3] | 8.3 [5.7, 10.2] | <0.001 |
Plasma (total) | 21.9 [17.2, 24.4] | −0.63 (−0.81 to −0.36) | 19.2 [16.1, 22.1] | 24.4 [18.9, 26.9] | 0.013 |
Plasma (unbound) | 18.5 [14.4, 21.1] | −0.66 (−0.82 to −0.39) | 15.9 [13.3, 18.7] | 21.1 [16.6, 23.3] | 0.007 |
t1/2 (hours) | |||||
ISF | 3.9 [2.8, 4.8] | 0.11 (−0.26 to 0.45) | 3.9 [2.7, 5.1] | 3.8 [3.0, 4.2] | 0.664 |
Plasma (total and unbound) | 3.4 [2.6, 4.4] | 0.52 (0.20 to 0.74) | 3.8 [3.0, 4.8] | 3.0 [2.5, 3.6] | 0.088 |
Vss (L), plasma | 37.7 [31.3, 44.6] | 0.87 (0.75 to 0.94) | 41.0 [38.4, 57.9] | 30.8 [27.9, 35.5] | <0.001 |
CL (L/h), plasma | 7.2 [6.3, 9.3] | 0.21 (−0.16 to 0.53) | 8.2 [6.2, 10.8] | 7.0 [6.4, 8.2] | 0.170 |
MRT (h), plasma | 5.0 [3.8, 6.3] | 0.47 (0.13 to 0. 71) | 5.7 [4.5, 6.9] | 4.4 [3.8, 5.4] | 0.079 |
Tmax, ISF 30–60/60–90/>90 min (number of patients) | 17/3/10 | — | 7/3/5 | 10/0/5 | 0.252 |
AUC0-8, (mg*h/L) | |||||
ISF | 29.4 [23.5, 37.8] | −0.61 (−0.80 to −0.32) | 23.7 [20.2, 28.1] | 34.4 [29.4, 45.5] | 0.004 |
Plasma (total) | 63.4 [52.8, 71.1] | −0.66 (−0.82 to −0.39) | 57.9 [45.4, 65.6] | 67.8 [61.5, 80.5] | 0.011 |
Plasma (unbound) | 54.5 [45.6, 61.5] | −0.68 (−0.84 to −0.43) | 47.7 [39.7, 56.7] | 59.6 [51.7, 70.8] | 0.005 |
AUC0–8 ISF/fAUC0–8 plasma | 0.53 [0.46, 0.65] | −0.28 (−0.58 to 0.09) | 0.53 [0.45, 0.55] | 0.62 [0.53, 0.68] | 0.080 |
All Patients (n = 30) | Pearson’s Correlation Coefficient with Weight | Obese (n = 15) | Non-Obese (n = 15) | p-Value | ||
---|---|---|---|---|---|---|
MIC (mg/L) | ||||||
fAUC24/MIC | ||||||
ISF | 0.5 | 176.8 [125.4, 218.2] | −0.47 (−0.71 to −0.13) | 140.0 [105.6, 207.0] | 182.4 [165.4, 239.6] | 0.033 |
1 | 88.4 [62.7, 109.1] | 70.0 [52.8, 103.5] | 91.2 [82.7, 119.8] | |||
2 | 44.2 [31.3, 54.6] | 35.0 [26.4, 51.7] | 45.6 [41.3, 59.9] | |||
4 | 22.1 [15.7, 27.3] | 17.5 [13.2, 25.9] | 22.8 [20.7, 30.0] | |||
plasma | 0.5 | 286.6 [220.8, 324.0] | −0.42 (−0.68 to −0.08) | 237.6 [199.8, 321.8] | 289.4 [250.0, 324.0] | 0.175 |
1 | 143.3 [110.4, 162.0] | 118.8 [99.9, 160.9] | 144.7 [125.0, 162.0] | |||
2 | 71.7 [55.2, 81.0] | 59.4 [49.9, 80.5] | 72.4 [62.5, 81.0] | |||
4 | 35.8 [27.6, 40.4] | 29.7 [25.0, 40.2] | 36.2 [31.3, 40.5] |
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Simon, P.; Busse, D.; Petroff, D.; Dorn, C.; Ehmann, L.; Hochstädt, S.; Girrbach, F.; Dietrich, A.; Zeitlinger, M.; Kees, F.; et al. Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study. J. Clin. Med. 2020, 9, 1067. https://doi.org/10.3390/jcm9041067
Simon P, Busse D, Petroff D, Dorn C, Ehmann L, Hochstädt S, Girrbach F, Dietrich A, Zeitlinger M, Kees F, et al. Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study. Journal of Clinical Medicine. 2020; 9(4):1067. https://doi.org/10.3390/jcm9041067
Chicago/Turabian StyleSimon, Philipp, David Busse, David Petroff, Christoph Dorn, Lisa Ehmann, Sophie Hochstädt, Felix Girrbach, Arne Dietrich, Markus Zeitlinger, Frieder Kees, and et al. 2020. "Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study" Journal of Clinical Medicine 9, no. 4: 1067. https://doi.org/10.3390/jcm9041067
APA StyleSimon, P., Busse, D., Petroff, D., Dorn, C., Ehmann, L., Hochstädt, S., Girrbach, F., Dietrich, A., Zeitlinger, M., Kees, F., Kloft, C., & Wrigge, H. (2020). Linezolid Concentrations in Plasma and Subcutaneous Tissue are Reduced in Obese Patients, Resulting in a Higher Risk of Underdosing in Critically Ill Patients: A Controlled Clinical Pharmacokinetic Study. Journal of Clinical Medicine, 9(4), 1067. https://doi.org/10.3390/jcm9041067