Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis

Abstract

Practitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

Amikacin target achievement in adult cystic fibrosis patients utilizing Monte Carlo simulation

“…Based on their patient population V d of 14.4 L and clearance of 3.06 L/h the calculated K e would be 0.2125 h −1 , which is within the standard deviation of our patient population with a K e of 0.23 ± 0.09 h −1 . The authors used a two‐compartment model with first‐order elimination and found creatinine clearance and weight to be significant covariates for clearance and V d , respectively, and further supports the notion that pharmacokinetics differ in patients with CF compared to patients without CF . Our study therefore reinforces the need to optimize initial aminoglycoside regimens by taking into account the patient‐specific V d .…”

“…In this study, the odds of achieving target peak concentrations were reduced as the V d increased . A recent study published by Illamola et al utilized data obtained from routine therapeutic drug monitoring to model population pharmacokinetics of amikacin in adult patients with CF . Based on their patient population V d of 14.4 L and clearance of 3.06 L/h the calculated K e would be 0.2125 h −1 , which is within the standard deviation of our patient population with a K e of 0.23 ± 0.09 h −1 .…”

“…A recent study published by Illamola et al utilized data obtained from routine therapeutic drug monitoring to model population pharmacokinetics of amikacin in adult patients with CF . Based on their patient population V d of 14.4 L and clearance of 3.06 L/h the calculated K e would be 0.2125 h −1 , which is within the standard deviation of our patient population with a K e of 0.23 ± 0.09 h −1 . The authors used a two‐compartment model with first‐order elimination and found creatinine clearance and weight to be significant covariates for clearance and V d , respectively, and further supports the notion that pharmacokinetics differ in patients with CF compared to patients without CF .…”

What is the recommended amikacin dosing for cystic fibrosis patients with acute pulmonary exacerbations?

“…As a consequence, in their study, they estimate a V d of 0.47 L/kg. In comparison, a much smaller V d of 0.24 L/kg was determined recently in a CF population of 49 adults . This value is similar to values previously described for other aminoglycosides in adult CF patients .…”

“…The PK of aminoglycosides is generally best described by two‐compartment models. Recently, a two‐compartment model with first‐order elimination was shown to best describe amikacin PK in CF patients . This study also showed the important influence of body weight on V d .…”