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Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis

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Abstract

The pharmacokinetics (PK) of β-lactam antibiotics in cystic fibrosis (CF) patients has been compared with that in healthy volunteers for over four decades; however, no quantitative models exist that explain the PK differences between CF patients and healthy volunteers in older and newer studies. Our aims were to critically evaluate these studies and explain the PK differences between CF patients and healthy volunteers. We reviewed all 16 studies that compared the PK of β-lactams between CF patients and healthy volunteers within the same study. Analysis of covariance (ANCOVA) models were developed. In four early studies that compared adolescent, lean CF patients with adult healthy volunteers, clearance (CL) in CF divided by that in healthy volunteers was 1.72 ± 0.90 (average ± standard deviation); in four additional studies comparing age-matched (primarily adult) CF patients with healthy volunteers, this ratio was 1.46 ± 0.16. The CL ratio was 1.15 ± 0.11 in all eight studies that compared CF patients and healthy volunteers who were matched in age, body size and body composition, or that employed allometric scaling by lean body mass (LBM). Volume of distribution was similar between subject groups after scaling by body size. For highly protein-bound β-lactams, the unbound fraction was up to 2.07-fold higher in older studies that compared presumably sicker CF patients with healthy volunteers. These protein-binding differences explained over half of the variance for the CL ratio (p < 0.0001, ANCOVA). Body size, body composition and lower protein binding in presumably sicker CF patients explained the PK alterations in this population. Dosing CF patients according to LBM seems suitable to achieve antibiotic target exposures.

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Acknowledgements

The authors thank Mr. Ingo Menhard for support with the graphics design, and Ms. Ann Ross for technical support during the submission of this review.

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  1. Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, 6550 Sanger Road, Office 475, Orlando, FL, 32827-7445, USA

    Jürgen B. Bulitta, Yuanyuan Jiao, Stefanie K. Drescher, Bartolome Moya & Xun Tao

  2. Servicio de Microbiología, Hospital Son Espases, Palma de Mallorca, Spain

    Antonio Oliver

  3. Institute for Therapeutic Innovation and Department of Medicine, College of Medicine, University of Florida, Orlando, FL, USA

    Arnold Louie & George L. Drusano

  4. Department of Visceral Surgery, University of Ulm, Ulm, Germany

    Mathias Wittau

  5. School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA

    Brian T. Tsuji

  6. Department of Internal Medicine, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    Alexandre P. Zavascki

  7. School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea

    Beom Soo Shin

  8. Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany

    Fritz Sörgel

  9. Department of Pharmacology, University of Duisburg-Essen, Essen, Germany

    Fritz Sörgel

  10. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia

    Cornelia B. Landersdorfer

Authors
  1. Jürgen B. Bulitta
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  2. Yuanyuan Jiao
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  3. Stefanie K. Drescher
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  4. Antonio Oliver
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  5. Arnold Louie
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  6. Bartolome Moya
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  7. Xun Tao
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  8. Mathias Wittau
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  9. Brian T. Tsuji
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  10. Alexandre P. Zavascki
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  11. Beom Soo Shin
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  12. George L. Drusano
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  13. Fritz Sörgel
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  14. Cornelia B. Landersdorfer
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Corresponding author

Correspondence to Jürgen B. Bulitta.

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Conflict of interest

Jürgen B. Bulitta, Yuanyuan Jiao, Stefanie K. Drescher, Antonio Oliver, Arnold Louie, Bartolome Moya, Xun Tao, Mathias Wittau, Brian T. Tsuji, Alexandre P. Zavascki, Beom Soo Shin, George L. Drusano, Fritz Sörgel, and Cornelia B. Landersdorfer declare no conflicts of interest relevant to the contents of this review.

Funding

This work was partly supported by Australian National Health and Medical Research Council (NHMRC) project grants (APP1045105 to JBB and CBL, and APP1101553 to CBL and JBB). NHMRC career development fellowships supported JBB (APP1084163) and CBL (APP1062509).

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Bulitta, J.B., Jiao, Y., Drescher, S.K. et al. Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis. Clin Pharmacokinet 58, 143–156 (2019). https://doi.org/10.1007/s40262-018-0678-x

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  • DOI: https://doi.org/10.1007/s40262-018-0678-x

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