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. 2022 Aug 22;14(8):1750.
doi: 10.3390/pharmaceutics14081750.

Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis

Jérémy Reverchon  1 , Vianney Tuloup  1   2 , Romain Garreau  1   2 , Viviane Nave  3 , Sabine Cohen  4 , Philippe Reix  2   5 , Stéphane Durupt  6 , Raphaele Nove-Josserand  6 , Isabelle Durieu  6   7 , Quitterie Reynaud  6   7 , Laurent Bourguignon  1   2   8 , Sandrine Charles  2 , Sylvain Goutelle  1   2   8
Affiliations

Implementation of Model-Based Dose Adjustment of Tobramycin in Adult Patients with Cystic Fibrosis

Jérémy Reverchon et al. Pharmaceutics. .

Abstract

Therapeutic drug monitoring (TDM) of tobramycin is widely performed in patients with cystic fibrosis (CF), but little is known about the value of model-informed precision dosing (MIPD) in this setting. We aim at reporting our experience with tobramycin MIPD in adult patients with CF. We analyzed data from adult patients with CF who received IV tobramycin and had model-guided TDM during the first year of implementation of MIPD. The predictive performance of a pharmacokinetic (PK) model was assessed. Observed maximal (Cmax) and minimal (Cmin) concentrations after initial dosing were compared with target values. We compared the initial doses and adjusted doses after model-based TDM, as well as renal function at the beginning and end of therapy. A total of 78 tobramycin courses were administered in 61 patients. After initial dosing set by physicians (mean, 9.2 ± 1.4 mg/kg), 68.8% of patients did not achieve the target Cmax ≥ 30 mg/L. The PK model fit the data very well, with a median absolute percentage error of 4.9%. MIPD was associated with a significant increase in tobramycin doses (p < 0.001) without significant change in renal function. Model-based dose suggestions were wellaccepted by the physicians and the expected target attainment for Cmax was 83%. To conclude, the implementation of MIPD was effective in changing prescribing practice and was not associated with nephrotoxic events in adult patients with CF.

Keywords: cystic fibrosis; model-informed precision dosing; pharmacokinetics; therapeutic drug monitoring; tobramycin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Organization of tobramycin therapy in our adult CF center. Abbreviations: Cmin, trough concentration; Cmax, maximal concentration; OPAT, outpatient parenteral antimicrobial therapy; PK, pharmacokinetics.
Figure 2
Figure 2
Observed concentrations of tobramycin versus individual model predictions. Blue circles represent observation/prediction pairs. The dashed blue line is the linear regression line. The solid line is the line of identity (y = x).
Figure 3
Figure 3
Violin plots of tobramycin doses before and after dose adjustment. The central solid line is the median. The black dotted lines are the quartiles (25th and 75th percentiles). Symbol **** indicates p < 0.0001.
Figure 4
Figure 4
Individual changes in serum creatinine during tobramycin therapy (n = 69). Abbreviation: ns, non-significant.
See this image and copyright information in PMC

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