A population approach to the forecasting of amikacin plasma and urinary levels using a prescribed dosage regimen

Abstract

We retrospectively analyzed amikacin pharmacokinetics in 19 critically ill patients who received amikacin intravenously. Fourteen subjects (577 serum amikacin concentrations, 167 urine measurements) were studied to obtain data for population modeling, while 5 patients (267 serum amikacin concentrations, 68 urine measurements) were studied for the assessment of predictive performance. The population analysis was performed using serum and urine amikacin measurements; the renal clearance of amikacin was expressed as a function of creatinine clearance. A two-compartment model was fitted to the population data by using NONMEM. The population characteristics of the pharmacokinetic parameters (fixed and random effects) were estimated using the FOCE method. The population pharmacokinetic parameters with the interindividual variability (CV%) were as follows: slope (0.254, 126%) and intercept (3 l/h, 59.6%) of the linear model which relate the amikacin renal clearance to the creatinine clearance, initial volume of distribution (17.1 l, 22.2%), intercompartment clearance (5.22 l/h, 104%), steady state volume of distribution (55.2 l, 64.1%) and urinary elimination (67.5%, 36.3%). The Bayesian approach developed in this study accurately predicts amikacin concentrations in serum and urine and allows for the estimation of amikacin pharmacokinetic parameters, minimizing the risk of bias in the prediction.

Amikacin in Critically Ill Patients: A Review of Population Pharmacokinetic Studies

“…Indeed, Garraffo et al showed that clearance was approximately 7.0 L/h and the volume of distribution was approximately 11.0 L in healthy volunteers receiving amikacin doses between 7.5 and 15 mg/kg [29]. Three out Table 4 continued References IIV Q (%) * Values are means of ten models described in this population contained fewer than 35 patients, which could limit the identification of a significant covariate [23,24,26]. Nevertheless, the models described in this population were able to identify some covariates with an effect on interindividual variability.…”

“…These pathophysiological changes leading to pharmacokinetic modifications could be included in the final model as covariates. A significant decrease in OFV and/or a significant decrease in the interindividual variability in clearance were obtained with creatinine clearance [19][20][21][22][23][24][25][26][27]. The effect of creatinine clearance on amikacin clearance was present in nine models.…”

“…However, only ten models have been described for amikacin in critically ill patients, using a nonlinear mixedeffects model [19][20][21][22][23][24][25][26][27][28]. Amikacin pharmacokinetics have been described by mono-exponential models as well as by bi-exponential models.…”

“…The studied populations consisted of critically ill patients with suspected Gram-negative infection, mainly septicaemia, pneumonia or severe trauma. Amikacin was administered as intermittent infusions according to different dosing regimens: once-daily dosing, twice-daily dosing or a dose interval adjusted according to a pharmacokinetic dosing method [19][20][21][22][23][24][25][26][27][28]. The doses administered ranged between 7.5 and 30 mg/kg/day ( ---data resulted in therapeutic drug monitoring.…”

“…Among these, 23 were excluded with reference to the inclusion and exclusion criteria. A total of ten articles were finally retained after three additional trials were added from reference scanning [19][20][21][22][23][24][25][26][27][28] (Fig. 1).…”