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Ther Drug Monit. 2020 Feb 11. doi: 10.1097/FTD.0000000000000743. [Epub ahead of print]

Does Circadian Rhythm affect the Pharmacokinetics of Once-Daily Tobramycin in Adults with Cystic Fibrosis?

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University Medical Center Utrecht, Clinical Pharmacy, Heidelberglaan 100, 3508 GA Utrecht, The Netherlands.
Haga Teaching Hospital, Pulmonary Diseases, Leyweg 275, 2545CH, The Hague, The Netherlands.
Maastricht University Medical Center, Clinical Pharmacy, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.
CAPRI, Maastricht, The Netherlands.
Central Pharmacy, The Hague, Clinical Pharmacy, Escamplaan 900, 2547 EX Den Haag, The Netherlands.



In the era of multiple daily dosing of systemic aminoglycosides, a circadian rhythm in the clearance of these vital antibiotics has been demonstrated in animals and healthy volunteers. Over the past decade, once-daily dosing regimens have been proved to be less nephrotoxic and were therefore adopted worldwide for most indications requiring treatment with an aminoglycoside. In this study, the effect of time of administration on the pharmacokinetics of once-daily tobramycin in adults with cystic fibrosis (CF) experiencing a pulmonary exacerbation was investigated.


In this open randomized study, patients with CF received intravenous tobramycin at 8:00 or 22:00 h. Pharmacokinetic and kidney function parameters were compared between the two groups.


Twenty-five patients were included. The mean weight-corrected clearances of tobramycin were 1.46 vs. 1.43 mL/h*kg (p=0.50) and mean volumes of distribution were 0.25 vs. 0.27 L/kg (p=0.54) for the 8:00 and 22:00 groups, respectively. In addition, no significant differences were detected in changes in estimated clearances of creatinine or tobramycin on day 1 and day 8 in the 8:00 or 22:00 group indicating that there was no decline in clearance over time. At day 8 of therapy, the increase in serum blood urea nitrogen in the 22:00 group was significantly higher than that in the 8:00 group (1.8 vs. 0.2 mmol/L, p=0.015).


The time of administration (8:00 vs 22:00) did not affect tobramycin pharmacokinetics in the adult CF population studied. The increase in serum blood urea nitrogen in the 22:00 group requires further investigation.

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