{'fraction_non_alphanumeric': 0.03369209171736079, 'fraction_numerical': 0.014974262985493684, 'mean_word_length': 5.03954802259887, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
New Recommendations of a Height-Based Dosing Regimen of Tobramycin for Cystic Fibrosis in Adults: A Population Pharmacokinetic Analysis.

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 re-evaluation 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 (Cmax) to the minimal inhibitory concentration (MIC) (Cmax/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 Cmax/MIC values ≥ 8 and ≥ 10, respectively. However, higher doses were required to achieve the AUC/MIC targets.


CONCLUSION
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 median height of 164 cm and weight of 55 kg to achieve the target plasma concentrations.