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Evaluation of Tobramycin Exposure Predictions in Three Bayesian Forecasting Programmes Compared with Current Clinical Practice in Children and Adults with Cystic Fibrosis

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Abstract

Background and Objectives

Bayesian forecasting (BF) methods for tobramycin dose individualisation has not seen widespread clinical adoption, despite being endorsed by clinical practice guidelines. Several freeware and commercial programmes using BF methods are available to support personalised dosing. This study evaluated exposure estimates, dose recommendations, and predictive performance compared with current clinical practice.

Methods

Data from 105 patients (50 adults and 55 children) with cystic fibrosis who received intravenous tobramycin treatment and had paired concentration–time measurements were analysed using (1) log-linear regression analysis, and (2) three BF programmes: TDMx, InsightRX, and DoseMe. Exposure estimates and dose recommendations were compared using the Wilcoxon signed-rank test and Bland–Altman analysis. Predictive performance of BF programmes was compared based on bias and imprecision.

Results

Median estimated tobramycin exposure with current clinical practice was significantly lower (87.8 vs. 92.5, 94.0 and 90.3 mg h l−1; p ≤ 0.01), hence median subsequent dose recommendations were significantly higher (10.1 vs. 9.4, 9.4 and 9.2 mg kg−1; p ≤ 0.01) compared with BF programmes. Furthermore, median relative dose-adjustment differences were higher in adults (> 10%) compared with children (4.4–7.8%), and differences in individual dose recommendations were > 20% on 19.1–27.4% of occasions. BF programmes showed low bias (< 7%) and imprecision (< 20%), and none of the programmes made consistently significantly different recommendations compared with each other.

Conclusions

On average, the predictions made by the BF programmes were similar, however substantial individual differences were observed for some patients. This suggests the need for detailed investigations of true tobramycin exposure.

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Acknowledgements

The authors would like to thank Elouise Jendra for help with the data collection, and Prof. Dr. Sebastian G. Wicha (TDMx), Dr. Ron Keizer (InsightRX) and the team of DoseMe for their ongoing software support.

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Authors and Affiliations

  1. School of Pharmacy, Pharmacy Australia Centre of Excellence, University of Queensland, 20 Cornwall Street, Woolloongabba, Brisbane, QLD, 4102, Australia

    Marc Burgard, Sonya Stacey & Stefanie Hennig

  2. Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, NSW, Australia

    Indy Sandaradura

  3. St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

    Indy Sandaradura

  4. Department of Microbiology and Infectious Diseases, Royal Prince Alfred Hospital, Sydney, NSW, Australia

    Sebastiaan J. van Hal

  5. Pharmacy Department, Children’s Health Queensland Hospital and Health Service, Lady Cilento Children’s Hospital, South Brisbane, QLD, Australia

    Sonya Stacey

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  1. Marc Burgard
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  4. Sonya Stacey
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Contributions

MB collected and analysed the data, and drafted the manuscript; IS, SvH and SS supported data collection, and undertook manuscript review; and SH conceived the study, supported data analysis, and wrote the manuscript.

Corresponding author

Correspondence to Stefanie Hennig.

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Funding

No sources of funding were used in the preparation of this article.

Conflict of interest

Marc Burgard, Indy Sandaradura, Sebastiaan J. van Hal, Sonya Stacey and Stefanie Hennig have no conflicts of interest to declare.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.

Electronic supplementary material

Below is the link to the electronic supplementary material.

40262_2017_610_MOESM1_ESM.tiff

Fig. S1 (a) Estimated daily area under the concentration-time curve (AUC0-24; n= 459) for 105 patients obtained using the LLR method (LLR, light green), TDMx (TDMx, light blue), InsightRX (IRX, orange) and DoseMe (DM, red). The black horizontal line represents the average target exposure for both hospitals of 100 mg∙h∙l-1. (b) Difference in predicted daily AUC0-24 obtained using TDMx (TDMx-LLR, light green), InsightRX (IRX-LLR, light blue) and DoseMe (DM-LLR, red) compared to the LLR method for the i th individual on the j th episode. The horizontal line represents a difference of zero between the predicted daily AUC0-24 given the LLR method and either of the BF programs. Three outliers have been excluded to increase readability. (c) Subsequent dose recommendation using LLR method (LLR, light green), TDMx (TDMx, light blue), InsightRX (IRX, orange) and DoseMe (DM, red). The black horizontal line represents current guideline initial dose recommendation of 10 mg/kg. (d) Relative difference in subsequent dose recommendation comparing the LLR method to TDMx (TDMx-LLR, light blue), InsightRX (IRX-LLR, orange) and DoseMe (DM-LLR, red) for a target drug exposure of 100 mg∙h∙l-1. The black horizontal line indicates no relative difference between the two methods compared. The boxes span the range between the first and third quartiles, with the median marked as a horizontal line. Whiskers represent the points within one-and-a-half interquartile ranges of the first and third quartile, which are represented at each end of the boxes. The individual dots represent outliers which lay more than one-and-a-half interquartile ranges outside of the interquartile range of the box plot. n total number of contributing concentration-time sets. (TIFF 2744 kb)

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Burgard, M., Sandaradura, I., van Hal, S.J. et al. Evaluation of Tobramycin Exposure Predictions in Three Bayesian Forecasting Programmes Compared with Current Clinical Practice in Children and Adults with Cystic Fibrosis. Clin Pharmacokinet 57, 1017–1027 (2018). https://doi.org/10.1007/s40262-017-0610-9

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  • DOI: https://doi.org/10.1007/s40262-017-0610-9

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