Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily

Abstract

Aims: 1. To determine the population pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. 2. To see if current starting doses for once daily aminoglycoside dosing are appropriate. 3. To test whether calculating creatinine clearance using an adjusted Cockcroft and Gault method (CLCr,adjusted ) was a better predictor of gentamicin clearance than the standard Cockcroft and Gault method (CLCr,unadjusted ).

Methods: Nine hundred and fifty-seven patients were dose-individualized for gentamicin using SeBA-GEN, a Bayesian dosing method. This method returns estimates of the values of gentamicin CL and V d from which the 24 h AUC can be estimated. The goal of therapy was to attain an AUC of 70-100 mg l-1 h depending on the severity of the infection. The population was divided into four groups of differing renal function. Linear regression analysis was performed to determine the relationship between V d and various indices of weight, and gentamicin CL and either CLCr,adjusted or CLCr,unadjusted.

Results: The mean V d (+/-s. d.) and CL (+/-s.d.) of gentamicin in our total population were 17.4 (+/-4.1) l and 4.0 (+/-1.8) l h-1, respectively. There was a decrease in V d with reducing renal function when comparing patients with normal renal function and patients with poor renal function. The lower of total body weight (TBW) and lean body weight (LBW), termed dosing weight (DWT), was a slightly better predictor of V d (r2=0.28) than either TBW (r2=0.21) or LBW (r2=0.21). CLCr,adjusted (r2=0.80) was a better predictor of gentamicin CL than CLCr, unadjusted (r2=0.57).

Conclusions: The mean population values of V d and CL of gentamicin dosed once daily are similar to those described by others in relation to multiple daily dosing. Given that previous methods have been based on population values of V d and CL from multiple daily dosing, the currently recommended starting doses for once daily aminoglycoside dosing would seem appropriate. The V d reduced with decreasing renal function, with a maximum of 23% difference between patients with normal and poor renal function. The Cockcroft and Gault method of calculating creatinine clearance does not appear to perform well at low values of serum creatinine concentration. An adjustment of the Cockcroft and Gault method is proposed to allow for this.

Figure 1

a) Frequency histogram of gentamicin CL for 957 patients. b) frequency histogram of V_d for 957 patients.

Figure 2

V_d (1) vs DWT (kg) where DWT is the lower of TBW or LBW. The solid line represents the line of best fit. The dashed lines represent the 95% confidence interval of the slope.

Figure 3

a) Gentamicin clearance vs CL_Cr,adjusted where values of serum creatinine less than 0.06 mmol l⁻¹ are set at 0.06 mmol l⁻¹ and DWT is used instead of LBW. b) Gentamicin clearance vs CL_Cr,adjusted using method of Cockcroft and Gault [19] but using DWT in stead of TBW. The solid line on both graphs represents the line of best fit. The dashed lines represent the 95% confidence interval of the slope.

Figure 4

A plot of the squared correlation coefficient from the linear regression analysis of gentamicin CL and CL_{Cr,unadjusted}vs serum creatinine ‘round up’ where the patients with low values of serum creatinine were sequentially increased in the analysis.