Circadian Rhythm in Gentamicin in multiple doses against single dose in human

Abstract

The circadian timing system is influenced by various factors, including physical, chemical, and motor activities that follow a 24-hour cycle in living organisms. Drug administration that depends on the circadian rhythm, synchronized with pharmacokinetic profiles, has been clinically shown to be an effective technique for lessening the undesirable effects of treatment and making the most of treatment outcomes (1,5,19). This simulation project aims to provide clarity about how the circadian rhythm influences the pharmacokinetic pattern and toxicity profile of numerous important drugs that have narrow therapeutic indexes, with a specific focus being on gentamicin. The main focus of the present study is on the randomized controlled trial by Nakano et al, Choi et al, and Dickson et al. as the primary articles (5,6,18). In addition, a systematic review of studies published between 1986 and 2024 focused on examining circadian pharmacokinetic changes and toxicity outcomes from gentamicin administration. The main focus of Nakano et al. was to investigate how time of day impacts the pharmacokinetics of gentamicin in humans, given its narrow therapeutic range and the need to avoid nephrotoxicity and ototoxicity (18; 27). A dose of 91.6 mg intramuscular was given to twenty-nine males. The results revealed that there were no significant differences in maximum concentration (Cmax) and time to reach maximum concentration (Tmax) among the dosing times. Nonetheless, there were significant differences in area under the curve (AUC) between the administration times (p < 0.05). There were variations in gentamicin pharmacokinetics based on the time of administration. Significant differences (p < 0.05) were observed in AUC, half-life, and clearance. The AUC follows a bell-shaped curve, peaking at 26.58 µg·hr/ml around the 12th hour and dropping to 19.06 µg·hr/ml at 0 hours. Clearance is lowest at the 10th hour and highest at the 23rd hour, leading to higher drug exposure at night. These variations impact dosing decisions, with elevated nighttime levels raising concerns about potential toxicity, such as nephrotoxicity and ototoxicity. The highest value was obtained at night (mean 18.5 ± 2.48 µg.hr/ml). At midnight, clearance (Cl) was significantly lower (4.26 ± 0.16 L/hr) in comparison to the morning (4.71 ± 0.25 L/hr). From these findings, it can be inferred that the clearance of gentamicin varies based on the time of the day, being lower at night, which prolongs its life, highlighting why it is crucial to take dosing schedule into account, particularly with regards to patients with renal impairment, to improve efficiency while minimizing toxicity.

The study explores how circadian rhythms influence the pharmacokinetics and toxicity of drugs, specifically focusing on gentamicin, which has a narrow therapeutic index. It reviews randomized controlled trials and a systematic review of studies from 1986 to 2024 to understand these effects.

The key findings from Nakano et al. reveal that while the maximum concentration (Cmax) and time to reach maximum concentration (Tmax) of gentamicin did not significantly vary by dosing time, there were notable differences in area under the curve (AUC), half-life, and clearance. The AUC followed a bell-shaped pattern, peaking at midday and dropping at night. Clearance was lowest at midnight, leading to higher drug exposure at night and raising concerns about increased toxicity, such as nephrotoxicity and ototoxicity. These results suggest that the timing of gentamicin administration should be carefully considered, especially in patients with renal impairment, to optimize efficacy and reduce toxicity.