Bayesian Forecasting for Intravenous Tobramycin Dosing in Adults With Cystic Fibrosis Using One Versus Two Serum Concentrations in a Dosing Interval

Abstract

Background: Intravenous tobramycin treatment requires therapeutic drug monitoring (TDM) to ensure safety and efficacy when used for prolonged treatment, as in infective exacerbations of cystic fibrosis. The 24-hour area under the concentration–time curve (AUC24) is widely used to guide dosing; however, there remains variability in practice around methods for its estimation. The objective of this study was to determine the potential for a sparse-sampling strategy using a single postinfusion tobramycin concentration and Bayesian forecasting to assess the AUC24 in routine practice. Methods: Adults with cystic fibrosis receiving once-daily tobramycin had paired concentrations measured 2 hours (c1) and 6 hours (c2) after the end of infusion as routine monitoring. AUC24 exposures were estimated using Tucuxi, a Bayesian forecasting application that incorporates a validated population pharmacokinetic model. Simulations were performed to estimate AUC24 using the full data set using c1 and c2, compared with estimates using depleted data sets (c1 or c2 only), with and without concentration data from earlier in the course. The agreement between each simulation condition and the reference was assessed graphically and numerically using the median difference (∆) AUC24 and (relative) root mean square error (rRMSE) as measures of bias and accuracy, respectively. Results: A total of 55 patients contributed 512 concentrations from 95 tobramycin courses and 256 TDM episodes. Single concentration methods performed well, with median ∆AUC24 <2 mg·h·L−1 and rRMSE of <15% for sequential c1 and c2 conditions. Conclusions: Bayesian forecasting implemented in Tucuxi, using single postinfusion concentrations taken 2–6 hours after tobramycin administration, yield similar exposure estimates to more intensive (two-sample) methods and are suitable for routine TDM practice.

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

“…19 Therefore, a one-point postinfusion analysis of tobramycin is recommended for therapeutic drug monitoring practice. 20 However, the previously published PPK models failed to fit our study population. 21 Therefore, in this study, the authors aimed to develop a novel PPK model to establish the optimal initial tobramycin dose to treat APEs in adult patients diagnosed with CF.…”

Implementation and Comparison of Two Pharmacometric Tools for Model-Based Therapeutic Drug Monitoring and Precision Dosing of Daptomycin

“…Tucuxi is a new software dedicated to the analysis of TDM results and individual dose adjustment (http://www. tucuxi.ch/, accessed 27 December 2021) [26].…”

PBPK Modeling and Simulation and Therapeutic Drug Monitoring: Possible Ways for Antibiotic Dose Adjustment

“…Though historically, TDM was mostly implemented to prevent toxic adverse effects, mainly for glycopeptides and aminoglycosides, the assessment of trough and peak concentrations is considered diagnostically and therapeutically important and strongly recommended for patients using the aforementioned antibiotics. Since the treatment of serious infections can imply the administration of high doses of antibiotics, an accumulation of these drugs in plasma is recurrent, often leading to toxic effects, and the value of TDM of these antibiotics has been demonstrated [73,74,[78][79][80][81][82][83][84][85][86]. Although TDM has been recommended for these antibiotics, it is still not a routine clinical practice for reasons still not systematically reviewed.…”