Therapeutic Monitoring of Plasma Digoxin for COVID-19 Patients Using a Simple UPLC-MS/MS Method

Background:: Cardiovascular diseases (CVD) were reported in 8% - 16% of patients with 2019 coronavirus disease (COVID-19). Digoxin was one of the main drugs to treat CVD. Objective:: The clinician applied for therapeutic drug monitoring (TDM) of digoxin according to the drug usage of the patients to monitor their concentration of digoxin , so as to avoid its toxic and side effects, and provide a theoretical reference for clinical usage of digoxin in patients with COVID-19. Methods:: A method for quantifying digoxin concentration in plasma with ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was developed . After a simple protein precipitation of plasma with methanol, digoxin and its internal standard (digoxin-d3) were detected in positive ion mode using multiple reaction monitoring .Results: Plasma digoxin in the range of 0.2 - 10 ng/mL had a good linearity. The UPLC-MS/MS method was validated with inter-run accuracies from 91.3% to 107.4% and precisions less than 13%. Nine plasma samples (5 at valley concentration and 4 at follow-up after stopping dosing) from three patients with COVID-19 were tested. The mean plasma digoxin concentration was 0.73 ng/mL (ranged from 0 to 1.31 ng/mL). Digoxin was detected at the concentration of 0.93 ng/mL after stopping drug administration for 14 days. Conclusion:: In this study, we established a simple UPLC-MS/MS method using protein-precipitation to perform TDM of digoxin in patients with COVID-19, and found that about 56% of digoxin plasma concentration was within the treatment window (0.8 - 2.0 ng/mL). Digoxin can be remained in the body for nearly 14 days in severe patients with COVID-19 after stopping dosing.

Plasma digoxin levels and ejection fraction in pediatric heart failure

Background Digoxin has long been prescribed in children with heartfailure, but its efficacy has not been evaluated. A previous study atthe Department of Child Health, Dr. Cipto Mangunkusumo Hospitalrevealed that plasma digoxin levels, following a maintenance doseof 15 μg/kg/d, were sub-therapeutic. Regarding its narrow margin ofsafety, the trend is to use digoxin in even lower dose. Thus, the drug’simpact on cardiac performance need to be evaluated.Objective To evaluate whether a lower maintenance dose of digoxin(10 μg/kg/d) is sufficient to achieve a therapeutic level and to assess forpossible correlations between plasma digoxin level and left ventricularejection fraction (LVEF) as well as fractional shortening (LVFS).Methods A cross-sectional study was conducted on 20 pediatricheart failure patients at the Department of Child Health, Dr. CiptoMangunkusumo Hospital, Jakarta, from January to May 2012. Plasmadigoxin levels were measured by ELISA method after one month ormore of treatment; LVEF and LVFS were measured by echocardiography.Correlations between plasma digoxin level and LVEF or LVFSwere analyzed by Spearman’s correlation test. The LVEF before andafter digoxin treatment were compared by paired T-test.Results Thirteen out of 20 patients had plasma digoxinlevels within therapeutic range (0.5-1.5 ng/mL; 95%CI0.599 to 0.898) and 7 had sub-therapeutic levels (<0.5 ng/mL; 95%CI 0.252 to 0.417). No significant correlationswere observed between plasma digoxin level and LVEF(r=-0.085; P=0.722) or LVFS (r=-0.105; P=0.659). There was asignificant increase in LVEF before [42.18 (SD 14.15)%] and afterdigoxin treatment [57.52 (SD 11.09)%], (P < 0.0001).Conclusion Most patients in this study have plasma digoxin levelswithin therapeutic range. There are no significant correlationsbetween plasma digoxin level at the time point of measurementand LVEF or LVFS. However, an increase of LVEF is observed inevery individual patients following digoxin treatment.

Study of digoxin use in a public health unit

Digoxin is used for heart failure associated to systolic dysfunction and high ventricular rate. It has a narrow therapeutic range and intoxication may occur due to drug interactions or comorbidities. The aim of this work was to study digoxin use in a public health unit delineating the profile of patients susceptible to digitalis intoxication. Medical records belonging to patients admitted to the cardiomyopathy ward of the health unit (2009-2010) and in use of digoxin were analyzed. Among 647 patients admitted, 185 individuals using digoxin and possessed records available. The registration of plasma digoxin concentration was found in 80 records and it was out of the therapeutic range in 42 patients (52.5%). This group of individuals was constituted mainly by males patients (79%), functional class III of heart failure (65%), exhibiting renal failure (33%). The evaluated sample reflects the epidemiology of heart failure in Brazil and, although pharmacotherapy had been according to Brazilian Guidelines, apparently the monitoring was not performed as recommended. This work highlighs the necessity of plasma digoxin constant monitoring during pharmacotherapy and the development of protocols that enable a safer use, especially in male patients, functional class III and with renal dysfunction.