Population Pharmacokinetic Analysis of Amikacin for Optimal Pharmacotherapy in Korean Patients with Nontuberculous Mycobacterial Pulmonary Disease

Abstract

Amikacin is used as a therapy for patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) who are resistant to macrolide antibiotics or have severe symptoms. This study aimed to characterize the pharmacokinetic properties of amikacin in patients with NTM-PD by developing a population pharmacokinetic model and to explore the optimal pharmacotherapy in patients with NTM-PD. For this study, all data were retrospectively collected. The amikacin pharmacokinetic properties were best described by a two-compartment model with first-order elimination. The estimated glomerular filtration rate and body weight were identified as significant covariates for clearance and the volume of distribution, respectively. A model-based simulation was conducted to explore the probability of reaching the target therapeutic range when various dose regimens were administered according to the body weight and renal function. The simulation results indicated that the amikacin dosage should be determined based on the body weight, and for patients who weigh over 70 kg, it is necessary to adjust the dose according to renal function. In conclusion, the optimal pharmacotherapy of amikacin for patients with NTM-PD was recommended based on the population pharmacokinetic model, which is expected to enable the personalization of drug therapy and improve the clinical outcomes of amikacin therapy.

Keywords: amikacin; nontuberculous mycobacterial pulmonary disease; population pharmacokinetics.

Figure 1

Goodness-of-fit plots of the final pharmacokinetic model. Open circles indicate observations; solid black lines are the lines of identity; red lines are the line of locally weighted scatterplot smoothing.

Figure 2

Prediction-corrected visual predictive check for the final population pharmacokinetic model. The solid circles represent the observed amikacin serum concentrations; the solid lines represent the 5th (blue), median (red), and 95th (blue) percentiles of the observed concentration; the dashed lines represent the 5th (blue), median (red), and 95th (blue) percentiles of the simulated concentration; the blue and red areas indicate the 90% confidence interval of the simulated concentrations of each percentile.

Figure 3

Probability of amikacin therapeutic target attainment from model-based simulations after the following amikacin once-daily dosing regimen on day 5; panel on top of bar plot represents the grade of renal function; Panel on right of bar plot represents the body weight group; Normal, eGFR ≥ 90 mL/min/1.73 m²; Mild, 60 ≤ eGFR ≤ 89 mL/min/1.73 m²; Moderate, 30 ≤ eGFR ≤ 59 mL/min/1.73 m²; Severe, 15 ≤ eGFR ≤ 29 mL/min/1.73 m²; ESRD, eGFR < 15 mL/min/1.73 m².

Figure 4

Box plot of predicted amikacin concentration following five times amikacin intravenous administration with 12 mg/kg once daily dosing regimen in various body weight patients with normal renal function. The dotted line represents the therapeutic range of C_trough (<4 µg/mL); the dot-dashed lines represent the therapeutic range of C_peak (35–45 µg/mL).