New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis

Abstract

Background: Acute pulmonary exacerbations (APEs) in patients with adult cystic fibrosis (CF) are treated with a beta-lactam and an aminoglycoside for activity against Pseudomonas aeruginosa (PA). Emerging drug resistance and changing pharmacokinetic profile in an aging population involve a reevaluation of tobramycin dosing recommendations. The objective of this study was to develop a population pharmacokinetic model and establish optimal dosing recommendations for tobramycin using Monte Carlo simulations.Methods: This retrospective clinical study and data collection were performed at the CF center of the McGill University Health Center (MUHC), Canada. Model development and simulations were performed using a nonlinear mixed-effect modeling approach (NONMEM, version 7.4.2). The ratios of maximal concentration (C max ) to the minimal inhibitory concentration (MIC) (C max /MIC $8 and $10) and area under the curve (AUC) to the MIC (AUC/MIC $70 and $100) were evaluated.Results: Adult patients with CF (n = 51) treated with tobramycin were included in the study. Plasma concentrations of tobramycin were obtained for 699 samples from the MUHC database. The two-compartmental model best described the pharmacokinetics of tobramycin. The association of patient height with the central volume of distribution significantly improved this model. Height, rather than weight, induced the best reduction in objective function.According to simulations, doses between 3.4 mg/cm and 4.4 mg/ cm were necessary to achieve C max /MIC values of $8 and $10, respectively. However, higher doses were required to achieve the AUC/MIC targets.Conclusions: This study demonstrated that height of the patients seems to be more suitable than their weight for dosing adjustments in adult patients with CF. According to this model, initial doses of tobramycin between 3.4 and 4.4 mg/cm should be recommended for patients with a median height of 164 cm and weight of 55 kg to achieve the target plasma concentrations.

Evaluation of Target Attainment for Tobramycin in Children and Adults with Cystic Fibrosis

“…It can be concluded that there is a need to re-evaluate the initial tobramycin dose based on present real-world data, as overall supratherapeutic peak tobramycin concentrations were prevalent in children and adults with CF, respectively. Over the last few decades, tremendous efforts have been made to develop, based on PKPD data, model-informed precision dosing (MIPD) [15,[27][28][29]. These PKPD models have resulted in, for example, an initial dose of tobramycin of 15 to 17.5 mg/kg/day in children [26].…”

Development and Evaluation of a Height-Based Tobramycin Initial Dosing Nomogram for the Treatment of Adult Cystic Fibrosis Pulmonary Exacerbations

“…Prediction-corrected visual predictive checks demonstrating that the model by Crass et al adequately described the IUCPQ-UL data have been previously published. 17 A prediction-corrected visual predictive check demonstrating that the model by Koloskoff et al 20 adequately described MUHC data showed that more than 90% of the observed concentrations were within the 95% confidence interval of the simulated concentrations.…”

“…The model developed by Koloskoff et al was chosen for nomogram development, given that simulations performed using the models by Koloskoff et al and Crass et al both showed converging recommendations on optimal height-normalized tobramycin dose for the treatment of PEx in a median patient in 2 distinct populations. 17,20 A nomogram was developed to depict the relationship between the doses necessary to attain various tobramycin peak concentration targets (15, 20, 25, and 30 mg/L) and height. The equation of the line for each target concentration was obtained using linear regression.…”

“…Tobramycin plasma concentrations, dosing regimens, infusion durations, sampling times, age, sex, height, weight, serum creatinine, co-medications, causative pathogen, number of visits, and duration of treatment were retrospectively collected. 17,20 Patients at MUHC and IUCPQ-UL were typically treated with an initial dose of 7.5 and 10 mg/kg total body weight (if body mass index ,30 kg/ m 2 , otherwise adjusted body weight is used), respectively, and adjusted according to TDM.…”

“…Height has been previously shown to be significantly more predictive of tobramycin PK than body weight in patients with CF. 18–20 A recent simulation study also found that height-based dosing regimens achieved several peak concentrations and 24-hour area under the concentration–time curve (AUC 0–24 ) targets more frequently and with less variability than standard dosing. 21 The reasons why height provides a better fit than other body size descriptors have been discussed previously.…”