Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis

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, Cornelia B. Landersdorfer

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)143-156
Number of pages14
JournalClinical Pharmacokinetics
Volume58
Issue number2
DOIs
Publication statusPublished - 6 Feb 2019

Cite this

Bulitta, Jürgen B. ; Jiao, Yuanyuan ; Drescher, Stefanie K. ; Oliver, Antonio ; Louie, Arnold ; Moya, Bartolome ; Tao, Xun ; Wittau, Mathias ; Tsuji, Brian T. ; Zavascki, Alexandre P. ; Shin, Beom Soo ; Drusano, George L. ; Sörgel, Fritz ; Landersdorfer, Cornelia B. / Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis. In: Clinical Pharmacokinetics. 2019 ; Vol. 58, No. 2. pp. 143-156.
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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.",
author = "Bulitta, {J{\"u}rgen B.} and Yuanyuan Jiao and Drescher, {Stefanie K.} and Antonio Oliver and Arnold Louie and Bartolome Moya and Xun Tao and Mathias Wittau and Tsuji, {Brian T.} and Zavascki, {Alexandre P.} and Shin, {Beom Soo} and Drusano, {George L.} and Fritz S{\"o}rgel and Landersdorfer, {Cornelia B.}",
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Bulitta, JB, Jiao, Y, Drescher, SK, Oliver, A, Louie, A, Moya, B, Tao, X, Wittau, M, Tsuji, BT, Zavascki, AP, Shin, BS, Drusano, GL, Sörgel, F & Landersdorfer, CB 2019, 'Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis' Clinical Pharmacokinetics, vol. 58, no. 2, pp. 143-156. https://doi.org/10.1007/s40262-018-0678-x

Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis. / Bulitta, Jürgen B.; Jiao, Yuanyuan; Drescher, Stefanie K.; Oliver, Antonio; Louie, Arnold; Moya, Bartolome; Tao, Xun; Wittau, Mathias; Tsuji, Brian T.; Zavascki, Alexandre P.; Shin, Beom Soo; Drusano, George L.; Sörgel, Fritz; Landersdorfer, Cornelia B.

In: Clinical Pharmacokinetics, Vol. 58, No. 2, 06.02.2019, p. 143-156.

Research output: Contribution to journalArticleResearchpeer-review

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Bulitta JB, Jiao Y, Drescher SK, Oliver A, Louie A, Moya B et al. Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis. Clinical Pharmacokinetics. 2019 Feb 6;58(2):143-156. https://doi.org/10.1007/s40262-018-0678-x