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Exploring the Relationship between FEV1 Loss and Recovery and Aminoglycoside Pharmacokinetics in Adult Patients with Cystic Fibrosis: Implications for Clinical Dosing Strategies.

Authors
  • Hoff, Brian M1
  • Scheetz, Marc H1, 2, 3
  • Jain, Manu4
  • Cullina, Joanne F5
  • Rhodes, Nathaniel J1, 2, 3
  • 1 Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois.
  • 2 Department of Pharmacy Practice, Midwestern University Chicago College of Pharmacy, Downers Grove, Illinois.
  • 3 Pharmacometrics Center of Excellence, Midwestern University Chicago College of Pharmacy, Downers Grove, Illinois.
  • 4 Division of Pulmonary and Critical Care Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
  • 5 Ann and Robert H. Lurie Children's Hospital, Chicago, Illinois.
Type
Published Article
Journal
Pharmacotherapy
Publication Date
Jun 01, 2020
Volume
40
Issue
6
Pages
584–591
Identifiers
DOI: 10.1002/phar.2399
PMID: 32259317
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Systemic aminoglycosides remain a cornerstone of treatment for cystic fibrosis (CF) pulmonary exacerbations (PEx); however, the impact of aminoglycoside pharmacokinetics (PK) on outcomes is not well defined in adult CF patients. Our objective was to assess the impact of increasing PK exposures on the clinical outcomes of PEx treatment in adult CF patients receiving high-dose and standard-dose extended-interval aminoglycosides. We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and forced expiratory volume over 1 second (FEV1 ) data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain area under the curve (AUC)0-24 hr , maximum concentration (Cmax0-24 hr ), and minimum concentration (Cmin0-24 hr ) estimates. The primary efficacy end point was a 90% recovery of baseline FEV1 by 30 days posttreatment. Toxicity included signs or symptoms of ototoxicity, vestibular toxicity, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis. The study included 51 patients who contributed 188 FEV1 observations. There were 3.0 ± 1.7 (mean ± SD) aminoglycoside concentrations per patient. The mean AUC0-24 hr , Cmax0-24 hr , and Cmin0-24 hr across all agents and patients were 156 ± 96 mg*hr/L, 29.9 ± 12.7 mg/L, and 0.35 ± 0.66 mg/L, respectively. A total of 42 amikacin-, gentamicin-, or tobramycin-treated patients contributed to the efficacy analysis, of whom 85.7% experienced recovery posttreatment. Of the 51 included patients, 6 (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24 hr nor Cmax0-24 hr was associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 . Increasing aminoglycoside AUC0-24 hr and Cmax0-24 hr were not associated with FEV1 during PEx treatment. Although individualizing aminoglycoside dosing in adult CF patients is necessary to minimize toxicity risk, more work is needed to define optimally safe and effective dosing strategies for this population. © 2020 Pharmacotherapy Publications, Inc.

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