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

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 (C_max/MIC > 10) and the ratio of area under the drug concentration-time curve/MIC over 24 h (AUC_0-24h/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 AUC_0-24h/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.

Figure 1

Scatter plot of gentamicin concentrations for the included 14 critically ill CRRT patients with different gentamicin dosing regimens.

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.