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Clin Pharmacokinet. 2018 Jun 23. doi: 10.1007/s40262-018-0678-x. [Epub ahead of print]

Four Decades of β-Lactam Antibiotic Pharmacokinetics in Cystic Fibrosis.

Author information

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. jbulitta@cop.ufl.edu.
2
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.
3
Servicio de Microbiología, Hospital Son Espases, Palma de Mallorca, Spain.
4
Institute for Therapeutic Innovation and Department of Medicine, College of Medicine, University of Florida, Orlando, FL, USA.
5
Department of Visceral Surgery, University of Ulm, Ulm, Germany.
6
School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA.
7
Department of Internal Medicine, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
8
School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, Korea.
9
Institute for Biomedical and Pharmaceutical Research, Nürnberg-Heroldsberg, Germany.
10
Department of Pharmacology, University of Duisburg-Essen, Essen, Germany.
11
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

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.

PMID:
29936678
DOI:
10.1007/s40262-018-0678-x

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