Exploring the relationship between FEV1 loss and recovery and aminoglycoside pharmacokinetics in adult patients with cystic fibrosis: implications for clinical dosing strategies.
Pharmacotherapy. 2020 Apr 07;:
Authors: Hoff BM, Scheetz MH, Jain M, Cullina JF, Rhodes NJ
OBJECTIVE: 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.
METHODS: We conducted a retrospective study of adult CF patients treated with an intravenous aminoglycoside for a PEx. Serum amikacin, gentamicin, and tobramycin levels and FEV1 data were used to evaluate exposure-response relationships. PK parameters were estimated using a Bayesian approach to obtain AUC0-24hr , Cmax0-24hr , Cmin0-24hr estimates. The primary efficacy endpoint was a 90% recovery of baseline FEV1 by 30 days post-treatment. Toxicity included signs or symptoms of ototoxicity, vestibular, or renal toxicity. Multivariate linear mixed-effects models of FEV1 were used for exposure-response analysis.
RESULTS: The study included 51 patients who contributed 188 FEV1 observations. There were 3.0±1.7 (mean±SD) aminoglycoside concentrations per patient. The mean AUC0-24hr , Cmax0-24hr , and Cmin0-24hr 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 post-treatment. Of the 51 included patients, six (11.8%) experienced seven toxicity events. In exploratory exposure-response analyses, neither AUC0-24hr nor Cmax0-24hr were associated with FEV1 values after adjusting for clinical covariates and baseline FEV1 .
CONCLUSIONS: Increasing aminoglycoside AUC0-24hr and Cmax0-24hr were not associated with FEV1 during PEx treatment. While 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.
PMID: 32259317 [PubMed – as supplied by publisher]