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Exploring the Relationship between FEV(1) Loss and Recovery and Aminoglycoside Pharmacokinetics in Adult Patients with Cystic Fibrosis: Implications for Clinical Dosing Strategies

Hoff, B. M.; Scheetz, M. H.; Jain, M.; Cullina, J. F.; Rhodes, N. J.

Pharmacotherapy. 2020 Apr 8; 40(6):584-591

Abstract

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 forced expiratory volume over 1 second (FEV(1) ) 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 (C(max0-24 hr) ), and minimum concentration (Cmin(0-24 hr) ) estimates. The primary efficacy end point was a 90% recovery of baseline FEV(1) by 30 days posttreatment. Toxicity included signs or symptoms of ototoxicity, vestibular toxicity, or renal toxicity. Multivariate linear mixed-effects models of FEV(1) were used for exposure-response analysis. RESULTS: The study included 51 patients who contributed 188 FEV(1) observations. There were 3.0 ± 1.7 (mean ± SD) aminoglycoside concentrations per patient. The mean AUC(0-24 hr) , C(max0-24 hr) , and C(min0-24 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 AUC(0-24 hr) nor C(max0-24 hr) was associated with FEV(1) values after adjusting for clinical covariates and baseline FEV(1) . CONCLUSIONS: Increasing aminoglycoside AUC(0-24 hr) and C(max0-24 hr) were not associated with FEV(1) 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.

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