Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis

• Published in: Clinical pharmacokinetics 2019-02, Vol.58 (2), p.143-156
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacokinetics; Antibiotics; Bacterial infections; beta-Lactams - pharmacokinetics; Body composition; Cystic fibrosis; Cystic Fibrosis - metabolism; Drug dosages; Humans; Infections; Internal Medicine; Medicine; Medicine & Public Health; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Pneumonia; Proteins; Review Article; Studies
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-018-0678-x

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