Area under the curve achievement of once daily tobramycin in children with cystic fibrosis during clinical care

Abstract

Background The area under the concentration‐time curve over 24 hours (AUC24) is frequently utilized to monitor tobramycin exposure in children with cystic fibrosis (CF). An understanding of exposure target achievement during clinical implementation of an AUC24 based approach in children is limited. Methods A retrospective chart review was performed in children with CF treated with once daily tobramycin and drug concentration monitoring at a pediatric CF center. During clinical care AUC24 was estimated using a traditional log‐linear regression approach (LLR). AUC24 was also estimated retrospectively using a pharmacokinetic model‐based Bayesian forecasting approach (BF). AUC24 achievement after both approaches were compared. Results In 77 treatment courses (mean age, 12.7 ± 5.0 years), a target AUC24 100 to 125 mg h/L was achieved after starting dose in 21 (27%) and after initial dose adjustment in 35 (45%). In the first 7 days of treatment, 24 (32%) required ≥3 dose adjustments, and the mean number of drug concentrations measured was 7.1 ± 3.2. Examination of a BF approach demonstrated adequate prediction of measured tobramycin concentrations (median bias −2.1% [95% CI −3.1 to −1.4]; median precision 7.6% [95% CI, 7.1%‐8.2%]). AUC24 estimates utilizing the BF approach were higher than the LLR approach with a mean difference of 6.4 mg h/L (95% CI, 4.8 to 8.0 mg h/L). Conclusions Achievement of a narrow AUC24 target is challenging during clinical care, and dose individualization is needed in most children with CF. Implementing a BF approach for estimating AUC24 in children with CF is supported.

Target attainment of extended-interval dosing of tobramycin in patients less than five years of age with cystic fibrosis: A pharmacokinetic analysis

“…In a retrospective study of 77 children with CF treated with once daily tobramycin at a mean dose of 12.5 mg/kg/day, Brockmeyer et al found that 52% met the AUC 24 target of 80-120 mg*h/L after the initial dose based on log-linear regression. 13 This is comparable to our analyses, in which 43-44% of simulated patients given 12-13 mg/kg/day met this AUC target with log-linear regression. Brockmeyer also utilized Bayesian forecasting, based on a two-compartment model, to estimate AUC 24 for each subject.…”

“…Brockmeyer also utilized Bayesian forecasting, based on a two-compartment model, to estimate AUC 24 for each subject. 13 Again, similar to our assessment, estimates of AUC 24 using Bayesian methods were higher than with log-linear regression (mean difference of 6.4 mg*h/L). 13 These findings have significant clinical ramifications.…”

“…In the absence of Bayesian methods, log-linear regression is often used for clinical TDM to estimate PK parameters and target attainment in individual patients. 13 Since this approach relies on assumptions of a one-compartment model with linear elimination, C max can be grossly underestimated for a two-compartment drug, as we found. The log-linear approach can also lead to significant differences in AUC 24 estimates compared to Bayesian methods.…”

“…The equations used for this approach are shown in the Supplemental Materials. The log-linear approach is used clinically for TDM at many institutions, 13 including ours, so this approach was called the "TDM Approach." The results of these two methods demonstrate differences between model expectations and clinical calculations in a real-world setting.…”

Cystic fibrosis year in review 2020: Section 2 pulmonary disease, infections, and inflammation

“…To optimize dosing, pharmacokinetics play an important role. A retrospective review of once‐daily tobramycin dosing studied the usage of 24 h AUC (AUC 24 ) and the feasibility of various predictive pharmacokinetic models 69 . Using the traditional narrow (vs. broad) target AUC 24 was remarked to be challenging, as multiple lab draws are required with the unclear clinical difference between the two.…”