Population Pharmacokinetics of Amikacin Administered Once Daily in Patients with Different Renal Functions

Abstract

The aim of this work was to evaluate the pharmacokinetics of amikacin in Mexican patients with different renal functions receiving once-daily dosing regimens and the influence of clinical and demographical covariates that may influence the optimization of this antibiotic. A prospective study was performed in a total of 63 patients with at least one determination of amikacin plasma concentration. Population pharmacokinetic (PK) parameters were estimated by nonlinear mixed-effects modeling; validations were performed for dosing recommendation purposes based on PK/pharmacodynamic simulations. The concentration-versus-time data were best described by a one-compartment open model with proportional interindividual variability associated with amikacin clearance (CL) and volume of distribution (V); residual error followed a homoscedastic trend. Creatinine clearance (CL_CR) and ideal body weight (IBW) demonstrated significant influence on amikacin CL and V, respectively. The final model [CL (liters/h) = 7.1 × (CL_CR/130)^0.84 and V (liters) = 20.3 × (IBW/68)^2.9] showed a mean prediction error of 0.11 mg/liter (95% confidence interval, -3.34, 3.55) in the validation performed in a different group of patients with similar characteristics. There is a wide variability in amikacin PK parameters in Mexican patients. This leads to inadequate dosing regimens, especially in patients with augmented renal clearance (CL_CR of >130 ml/min). Optimization based on the final population PK model in Mexican patients may be useful, since reliability and clinical applicability have been demonstrated in this study.

Keywords: PK/PD modeling; amikacin; augmented renal clearance; population pharmacokinetics.

FIG 1

Scatterplots of goodness of fit of population and individual predicted versus observed amikacin concentrations (including the identity line) for the final one-compartment open model for critically ill patients receiving amikacin administered once daily by intermittent intravenous infusion (n = 50).

FIG 2

Visual predictive check for amikacin plasma concentration-time profiles. Solid lines represent the median (red) and the 95th and 5th percentiles (blue) of the observations, which are overlapped by the 90% confidence intervals for the median (red area) and the 95th and 5th percentiles (blue areas) of the simulated profiles (n = 1,000).

FIG 3

Amikacin dose suggested for critically ill patients based on final population pharmacokinetic model and bacterial MIC (n = 1,000 PK/PD simulations).