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. 2022 Jan 6:16:13-22.
doi: 10.2147/DDDT.S343385. eCollection 2022.

Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Sha He  1 , Zeneng Cheng  1 , Feifan Xie  1
Affiliations

Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy

Sha He et al. Drug Des Devel Ther. .

Abstract

Purpose: Appropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK) model of gentamicin in CRRT patients and to infer the optimal dosing regimen for gentamicin.

Methods: Fourteen CRRT patients dosed with gentamicin were included to establish a population PK model to characterize the variabilities and influential covariates of gentamicin. The pharmacokinetic/pharmacodynamic (PK/PD) target attainment and risk of toxicity for different combinations of gentamicin regimens (3-7 mg/kg q24h) and CRRT effluent doses (30-50 mL/h/kg) were evaluated by Monte Carlo simulation. The probability of target attainment (PTA) was determined for the PK/PD indices of the ratio of drug peak concentration/minimum inhibitory concentration (Cmax/MIC > 10) and the ratio of area under the drug concentration-time curve/MIC over 24 h (AUC0-24h/MIC > 100), and the risk of toxicity was estimated by drug trough concentration thresholds (1 and 2 mg/L).

Results: A one-compartment model adequately described the PK characteristics of gentamicin. Covariates including body weight, age, gender, and CRRT modality did not influence the PK parameters of gentamicin based on our dataset. All studied gentamicin regimens failed to achieve satisfactory PTAs for pathogens with an MIC ≥2 mg/L. A good balance of PK/PD target attainment and risk of toxicity (>2 mg/L) was achieved under 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose for an MIC ≤1 mg/L. CRRT dose intensity had a significant impact on the target attainment of AUC0-24h/MIC >100 and risk of toxicity.

Conclusion: A combination of 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose might be considered as a starting treatment option for CRRT patients, and drug monitoring is required to manage toxicity.

Keywords: CRRT; critically ill; gentamicin; population pharmacokinetics.

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Conflict of interest statement

The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Scatter plot of gentamicin concentrations for the included 14 critically ill CRRT patients with different gentamicin dosing regimens.
Figure 2
Figure 2
Goodness-of-fit plots of the final gentamicin population pharmacokinetic model. Top left panel: observed concentrations versus individual predictions of gentamicin in plasma. Top right panel: observed concentrations versus population predictions of gentamicin in plasma. Bottom left panel: conditional weighted residuals (CWRES) versus population predicted gentamicin concentrations. Bottom right panel: CWRES versus Time after dose.
See this image and copyright information in PMC

References

    1. Genga KR, Russell JA. Update of sepsis in the intensive care unit. J Innate Immun. 2017;9(5):441–455. doi: 10.1159/000477419 - DOI - PMC - PubMed
    1. Fleischmann-Struzek C, Mellhammar L, Rose N, et al. Incidence and mortality of hospital- and ICU-treated sepsis: results from an updated and expanded systematic review and meta-analysis. Intensive Care Med. 2020;46(8):1552–1562. doi: 10.1007/s00134-020-06151-x - DOI - PMC - PubMed
    1. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Crit Care Med. 2003;31(12):2742–2751. doi: 10.1097/01.CCM.0000098031.24329.10 - DOI - PubMed
    1. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–1596. doi: 10.1097/01.CCM.0000217961.75225.E9 - DOI - PubMed
    1. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Crit Care Med. 2021;49(11):e1063–e1143. doi: 10.1097/CCM.0000000000005337 - DOI - PubMed