Steady-state Digoxin Concentrations Research Articles

In Vitro P-Glycoprotein Interactions and Steady-State Pharmacokinetic Interactions Between Tolvaptan and Digoxin in Healthy Subjects

Interactions between tolvaptan and digoxin were determined in an open-label, sequential study where 14 healthy subjects received tolvaptan 60 mg once daily (QD) on days 1 and 12 to 16 and digoxin 0.25 mg QD on days 5 to 16. Mean maximal concentrations (C(max)) and area under the curve during the dosing interval (AUC(τ)) for digoxin with tolvaptan (day 16) were increased 1.27- and 1.18-fold compared with digoxin alone (day 11); mean renal clearance of digoxin was decreased by 59% (P < .05). Tolvaptan C(max) and AUC(0-24h) for a single dose with digoxin (day 12) were each increased about 10% compared with tolvaptan alone (day 1). Tolvaptan did not accumulate upon multiple dosing. After a single dose of tolvaptan (day 1, day 12), 24-hour urine volume was about 7.5 L. As expected, after 5 days of tolvaptan, 24-hour urine volume decreased about 20%. In vitro studies in control and MDR1-expressing LLC-PK1 cells indicate that tolvaptan is a substrate of P-glycoprotein. Tolvaptan (50 µM) inhibited basolateral to apical digoxin secretion to the same extent as 30 µM verapamil; the IC50 of tolvaptan was determined to be 15.9 µM. The increase in steady-state digoxin concentrations is likely mediated by tolvaptan inhibition of digoxin secretion.

A Method of Determining the Dose of Digoxin for Heart Failure in the Modern Era

The therapeutic range for digoxin in heart failure has recently changed to become lower and narrower, and the new range is associated with improved mortality. However, dosing methods have not been modified to reflect this change. In this study, we sought to develop a new method to determine the initial dose of digoxin in patients with heart failure. Over a 6-month period, medical records were screened and reviewed for hospitalized adult patients who had a steady state digoxin concentration. A multiple linear regression was estimated relating digoxin concentration, digoxin dose, creatinine clearance, and ideal body weight to generate an equation relating the dose of digoxin with these variables and a specific target digoxin concentration of 0.7 ng/mL (0.9 nmol/L). This new method was then compared with 2 existing methods. Included in the study were 54 patients (mean [SD] age, 68 [15] years, with a mean (SD) creatinine clearance of 50 (25) mL/min (0.8 [0.4] mL/s) and mean (SD) ideal body weight of 62 (11) kg. Our proposed method and the Jusko and Koup method were more accurate than the Jelliffe method in predicting digoxin concentration. Root mean square errors were as follows: for the Jelliffe method (using ideal body weight), 0.810; for the Koup and Jusko method (with heart failure), 0.401; our proposed method, 0.375. The proposed method was then used to create a dosing nomogram. Because the new therapeutic window of digoxin is associated with improved outcomes, more intensive dosage refinement should be considered. To this end, we offer new dosing recommendations and a nomogram for determining the initial dose of digoxin in patients with heart failure.

Contemporary Use of Digoxin in the Management of Cardiovascular Disorders

Digitalis is the oldest compound in cardiovascular medicine that continues to be used in contemporary clinical practice.1 Evidence supporting the beneficial effects of digoxin on hemodynamic, neurohormonal, and electrophysiological parameters has been accumulated from >200 years of clinical experience and research (Table 1).2 View this table: TABLE 1. Effects of Digoxin Digoxin was approved for heart failure in 1998 under current regulations by the Food and Drug Administration on the basis of the Prospective Randomized Study of Ventricular Function and Efficacy of Digoxin (PROVED), Randomized Assessment of Digoxin on Inhibitors of the Angiotensin Converting Enzyme (RADIANCE), and Digitalis Investigators Group (DIG) clinical trials.3–5 It was also approved for the control of ventricular response rate for patients with atrial fibrillation. The most recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend digoxin for symptomatic chronic heart failure for patients with reduced systolic function (Class IIa recommendation: weight of evidence/opinion is in favor of usefulness/efficacy), preserved systolic function (Class IIb: usefulness/efficacy is less well established by evidence/opinion), and/or rate control for atrial fibrillation with a rapid ventricular response (Class IIa).6 The new Heart Failure Society of America guidelines for heart failure provide similar recommendations.7 Despite its relatively recent approval by the Food and Drug Administration and the guideline recommendations, digoxin use is decreasing in patients with heart failure.8 In the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF) registry, only 30% of patients with left ventricular systolic dysfunction were being treated with digoxin before admission. Digoxin was added in only 8% of patients before discharge despite the fact that they had signs and symptoms of heart failure while receiving diuretics, ACE inhibitors, or angiotensin receptor blockers (ARBs) and β-blockers.9,10 This decrease in digoxin use is likely the result of several factors. …

Effect of Clarithromycin on Steady-State Digoxin Concentrations

Effect of Clarithromycin on Steady-State Digoxin Concentrations

Effect of Clarithromycin on Steady-State Digoxin Concentrations

Effect of Clarithromycin on Steady-State Digoxin Concentrations

Population-based investigation of relative clearance of digoxin in Japanese neonates and infants by multiple-trough screen analysis

The steady-state concentrations of digoxin at trough levels were studied to establish the role of patient characteristics in estimating doses for digoxin using routine therapeutic drug monitoring data. The data (n = 448) showing steady state after repetitive oral administration in 172 hospitalized neonates and infants were analyzed using Nonlinear Mixed Effect Model (NONMEM), a computer program designed to analyze pharmacokinetics in study populations by allowing pooling of data. Analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of digoxin were investigated. Estimates generated using NONMEM indicated that clearance of digoxin (l.h-1) was influenced by the demographic variables of age, total body weight, serum creatinine, the coadministration of spironolactone, and the presence or absence of congestive heart failure. The interindividual variability in digoxin clearance was modeled with proportional errors with an estimated coefficient of variation of 32.1%, and the residual variability was 28.9%. In the validation set of 66 patients, the performance (bias, precision) of the final population model was good (mean prediction error -0.04 ng.ml-1; mean absolute prediction error 0.20 ng.ml-1).

Factors Influencing the Prediction of Steady State Concentrations of Digoxin.

The prediction error in the Bayesian analysis program for digoxin was evaluated in Japanese patients, and factors influencing the accuracy were investigated. Serum concentrations of digoxin were monitored two times and were compared with the predicted values obtained by using the Bayesian analysis program. The prediction error at the first time was 43.1%. Although this estimation error was reasonably restored at the second time of monitoring, the prediction error remained at 26.6%. These data suggested that unknown factors not included in the program affected the serum concentration of digoxin. Retrospective research of the digoxin serum concentrations in the patients suggested the coadministration of the drugs, which were the P-glycoprotein modulators, as well as the unexpected alteration of the serum creatinine, were the important factors influencing the prediction of the drug serum concentrations. We next examined the inhibitory effect of quinidine, verapamil and spironolactone on the transcellular transport of digoxin by using human P-glycoprotein overexpressing LLC-GA5-COL150 cells. Quinidine, verapamil and spironolactone could inhibit the transcellular transport of digoxin by 50%. In addition, the reduction of the renal clearance by 50%, which could possibly be caused by this inhibition, led to the increase of 36% in the steady state through concentrations of digoxin in the physiological pharmacokinetic model. In conclusion, the prediction of long-term serum concentration-time profiles of digoxin, based on the Bayesian analysis, will be disturbed by the coadministration of the P-glycoprotein modulators and the unexpected alteration of the serum creatinine.

乳児心不全患者のジゴキシン母集団薬物動態解析

The steady-state concentrations of digoxin at trough levels were studied to establish the role of infant characteristics in estimating the doses for digoxin based on routine therapeutic drug monitoring data. The data (n = 340) which showed a steady-state after repetitive oral administration in 147 hospitalized infants were analyzed using NONMEM, a computer program designed to analyze the pharmacokinetics in study populations by allowing for the pooling of data. An analysis of the pharmacokinetics of digoxin was accomplished using a simple steady-state pharmacokinetic model. The effects of a variety of developmental and demographic factors on the clearance of digoxin were investigated. Estimates generated using NONMEM indicated that the clearance of digoxin (L/hr/kg) was influenced by the demographic variables of age, the daily dose, serum creatinine, the presence or absence of congestive heart failure, and the coadministration of spironolactone in infants. The interindividual variability in the clearance of digoxin was modeled using proportional errors with an estimated coefficient of variation of 30.2%, while the residual variability was 28.2%.

Comparison of Steady-State Serum Concentrations of Digoxin in Tablets (Lanoxin) and Capsules (Lanoxicaps) in the Elderly

The bioavailability of digoxin in solution (Lanoxicaps, 90-100 percent) is superior to that of Lanoxin tablets (60-80 percent) in young healthy volunteers. The alleged bioequivalence of digoxin in tablets (Lanoxin 0.25, 0.125 mg) and capsules (Lanoxicaps 0.2, 0.1 mg) was studied in 20 elderly inpatients (14 women, 6 men, aged 84 +/- 5 years), treated with digoxin for atrial fibrillation. In a crossover design, steady-state digoxin concentrations were measured in 16 patients after once-daily administration of Lanoxin 0.125 mg or Lanoxicaps 0.1 mg, each for at least ten days. Four other patients took Lanoxin 0.25 mg and Lanoxicaps 0.2 mg successively. The steady-state digoxin concentrations were statistically significantly different, being 1.3 +/- 0.5 nmol/L for Lanoxin and 0.9 +/- 0.4 nmol/L for Lanoxicaps (p = 0.003). Whereas in young healthy volunteers the bioavailability of digoxin from Lanoxicaps (90-100 percent) exceeds that from Lanoxin (80 percent), in elderly patients the absorption appears to be similar. This suggests a lower than expected bioavailability of Lanoxicaps, which may result in subtherapeutic serum concentrations.

Steady‐state concentrations and dosage of digoxin in relation to kidney function in hospitalized patients over 70 years of age

Steady-state serum digoxin concentrations were determined and related to renal function in 62 hospitalized patients 70-93 years of age. Renal function was assessed by serum creatinine concentration, and creatinine clearance was estimated by a formula employing the serum creatinine concentration and adjusting for body weight, sex and age. The steady-state digoxin concentration was inversely related to the estimated creatinine clearance. As there was no correlation between serum creatinine and age, a simplified estimation of creatinine clearance capacity, disregarding age and sex and allowing only for body weight and serum creatinine, was applied. It is suggested that this simplified calculation is suitable for bedside use. If the body weight/serum creatinine ratio is less than 0.5 (kg x 1/mumol), approximately one-third of our patients would have digoxin concentrations that are close to or above the upper reference limit (2.6 nmol l-1) at the maintenance dose of 0.13 mg digoxin daily. A digoxin dose of 0.07 mg daily thus appears to be suitable for many patients aged greater than 70 years when the body weight/serum creatinine ratio is less than 0.5, and also when the serum creatinine level is normal or only slightly elevated. The half-life of digoxin in serum was determined in 12 patients for whom digoxin treatment was withdrawn due to clinical signs of intoxication, and these half-lives were markedly prolonged: 3.5-6 days at a body weight/serum creatinine ratio of 0.5-0.3. The seven patients with prolonged half-lives had serum creatinine concentrations in the range of 80-140 mumol l-1.

Effect of Cimetidine on Oral Digoxin Absorption

Cimetidine is a commonly prescribed histamine 2-receptor antagonist used in the treatment of gastric acid-related disorders. Cimetidine can interact with a number of drugs, including theophylline, benzodiazepine sedative hypnotics, warfarin, and antiarrhythmics. Problems may occur in patients receiving drugs with a narrow therapeutic index when combined with cimetidine. Contrasting reports have been published on the potential interaction between digoxin and cimetidine. This study focuses on cimetidine's effect on the pharmacokinetic disposition of chronic digoxin usage. Six hospitalized patients with stable congestive heart failure received their usual maintenance dose of digoxin 0.125-0.25 mg/d po. After confirming steady-state digoxin concentrations, cimetidine 300 mg po q6h was administered. Two patients were dropped from the study. Analysis of digoxin serum concentrations, area under the curve, and the rate of elimination suggested no significant differences in digoxin parameters when combined with cimetidine.

The effect of everyday exercise on steady state digoxin concentrations.

The purpose of this study was to evaluate the effect of 1 hour of everyday exercise (walking at patient's own pace) on serum digoxin concentrations. Nine white male subjects (ages 58-74) who had been taking the same digoxin dose for greater than 1 month participated. There were three continuous phases: 1 hour of rest, 1 hour of exercise, and a final hour of rest. Serum digoxin concentrations were drawn every 20 minutes. During the first rest period, serum digoxin concentrations rose 30% from the first concentration drawn in the study. After 1 hour of exercise, serum digoxin concentrations fell 26.8% from the last concentration of the first rest period. At the end of the second hour of rest, serum digoxin concentrations increased by 36.6% from the last concentration. Repeated measures analysis of variance demonstrated a significant (P less than .01) change in serum digoxin concentrations. Significant (P less than .01) differences were found between sampling times 0 and 60, 60 and 80, 60 and 100, 60 and 120 and 180 minutes using a paired t-test with Bonferroni correction. A weak correlation (r = 0.74, r2 = 0.55) between percent change in concentrations and age during the exercise phase was found, but there was no correlation between the percent change in concentrations and age during the two immobilization phases. Because significant changes in concentrations occurred during each phase of the study, we conclude that the influence of everyday exercise should be taken into account when interpreting serum digoxin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Physical Exercise on the Pharmacokinetics of Digoxin During Maintenance Treatment

Blood samples were taken repeatedly and urine was collected for digoxin assays on two occasions from 12 healthy male volunteers after an oral maintenance dose of digoxin. On one occasion the subjects exercised intermittently on a bicycle ergometer for 8 h after the dose. On the other occasion they rested in the supine position during the study period. Thirty and 45 min after the intake of digoxin, the serum digoxin concentration was significantly higher during exercise compared with rest, indicating increased absorption rate during exercise. Two and 4 h after the intake of digoxin, the serum digoxin concentration was significantly lower during exercise than during rest. Furthermore, the intermittent bicycle exercise decreased the renal excretion of digoxin during the study period. It also increased the steady state digoxin concentration measured after a terminating standardized period of rest. The most probable reason for these changes in the pharmacokinetics is a previously described increased binding of digoxin to exercising muscles. According to the results, there is reason to believe that the daily physical activity performed by digoxin-treated patients will determine to some extent the body content of digoxin. Changes in activity from day to day may therefore cause variations in the effect of the drug.

Effects of Amlodipine on Steady-State Digoxin Concentrations and Renal Digoxin Clearance

The effect of oral amlodipine on steady-state digoxin concentrations and renal clearance was studied in 21 healthy male subjects. After 2-week digitalization (digoxin, 0.375 mg/day), they were randomized in a single-blind crossover protocol to receive either placebo or amlodipine (5 mg/day) in combination with digoxin for the following two 2-week periods. Mean (+/- SD) digoxin concentrations of 0.64 +/- 0.19 ng/ml after 2-week digoxin monotherapy and 0.61 +/- 0.23 ng/ml during placebo were not altered by amlodipine (0.60 +/- 0.18 mg/ml). Renal digoxin clearance was 202 +/- 44 ml/min on placebo and 207 +/- 55 ml/min during amlodipine coadministration. No change in pharmacologic effect of digoxin was noted during amlodipine coadministration, nor was blood pressure or heart rate changed. These data indicate that oral amlodipine does not significantly influence steady-state digoxin concentrations in healthy subjects.

Effect of oral cibenzoline on steady-state digoxin concentrations in healthy volunteers.

The effect of oral cibenzoline on steady-state digoxin concentrations was studied in 12 healthy subjects ranging from 41 to 55 years of age. Each subject received an oral dose of 0.25 mg or 0.375 mg digoxin once daily for 27 days. On days 14 to 21, 160 mg of oral cibenzoline were administered concomitantly every 12 hours for a total of 15 doses. Plasma digoxin concentration-time profiles obtained before, during, and after cibenzoline coadministration were compared to determine the effect of oral cibenzoline on steady-state digoxin concentrations. The maximum plasma concentration, time of maximum concentration, area under the curve during a dosing interval and steady-state trough plasma concentration for digoxin, during and after concomitant doses of cibenzoline were similar to those before administration, indicating that cibenzoline did not affect the pharmacokinetics of digoxin. In addition, plasma cibenzoline concentration-time profiles after the first and last dose of cibenzoline were similar to those observed in previous studies in which multiple doses of cibenzoline alone were administered. The results of this study indicate that there is no pharmacokinetic interaction between digoxin and cibenzoline when the two drugs are coadministered to healthy subjects in multiple doses.

Diltiazem increases steady state digoxin serum levels in patients with cardiac disease.

Diltiazem has been reported to decrease or not to affect digoxin elimination. The effects of diltiazem on steady state concentrations of digoxin was evaluated in eleven patients with congestive heart failure receiving this drug for at least two weeks. The mean trough digoxin was 1.11 +/- 0.18 ng/ml before the coadministration of diltiazem (180 mg/day). This concentration increased to 1.54 +/- 0.22 ng/ml after three days and to 1.54 +/- 0.23 ng/ml after seven days of coadministration (P less than 0.01). Clinically, no patient showed signs of digitalis toxicity. Creatinine clearance was unchanged. The present results show that when diltiazem is added to a regimen that includes digoxin, steady state concentrations of this glycoside may increase.

Study of Pharmacokinetic and Pharmacodynamic Interaction between Nitrendipine and Digoxin

Nitrendipine is a new dihydropyridine-type calcium antagonist. We studied the effect of 20 mg b.i.d., orally, on steady-state digoxin concentrations, renal excretion, and hemodynamic parameters in 10 healthy male volunteers. A loading dose of 0.6 mg β-acetyldigoxin was given on days 1, 2, and 3. β-acetyldigoxin, 0.3 mg once daily, was given from day 4 to day 29 of the study. Nitrendipine coadministration lasted from day 9 until day 22. Equilibrium was assumed for days 6–8 (monotherapy), 20–22 (coadministration), and 27–29 (monotherapy after nifedipine withdrawal). Means and 95% confidence intervals of the treatment periods were compared. Digoxin concentrations slightly decreased from 0.7 ± 0.15 to 0.64 ± 0.14 and 0.59 ± 0.1 (mean ± SD). Urinary excretion during 24 h was fairly constant and did not show a remarkable effect of nitrendipine coadministration or withdrawal. The amounts excreted were 197.8 ± 19.1 (monotherapy), 193.2 ± 30.2 (coadministration), and 182.5 ± 31.8 μg/24 h. Renal digoxin clearance was 2.7 ± 0.4 and 2.9, ± 0.4 ml/min/kg on monotherapy and 2.9 ± 0.4 ml/min/kg on coadministration. Hemodynamic changes were small and not clinically relevant. They did not reflect an effect of nitrendipine.

Effects of nifedipine and diltiazem on plasma levels and renal excretion of beta-acetyldigoxin.

To determine whether nifedipine or diltiazem affect digoxin kinetics, glycoside plasma concentrations and renal excretion were measured before and during dosing in 23 patients with cardiac insufficiency achieving steady-state conditions. Mean (+/- SD) digoxin plasma concentration was 0.64 +/- 0.22 before and 0.61 +/- 0.21 ng/ml during nifedipine dosing in 11 subjects over a period of 10 to 14 days. Renal digoxin clearance was not influenced by nifedipine, whereas total body clearance and extrarenal clearance of digoxin increased slightly. In contrast, diltiazem resulted in a 24% to 70% (means = 46%) increase in plasma digoxin concentrations in eight of 12 subjects. Renal digoxin clearance was not influenced by diltiazem, whereas total body clearance and extrarenal clearance of digoxin were reduced 28% and 44% in five of the eight subjects in whom renal digoxin excretion was measured. From these data it was concluded that nifedipine has no significant effects on digoxin kinetics, but that digoxin plasma concentrations should be controlled in subjects receiving digoxin with diltiazem until new steady-state digoxin concentrations are established, and that the digoxin dose be reduced if there is evidence of toxicity.

Serum digoxin concentrations in a representative digoxin-consuming adult population.

As part of health examination of a representative sample of an adult population (n = 8000) serum digoxin concentration was measured in 661 patients on continuous digoxin therapy. The prescribed mean daily dose of digoxin was significantly higher in men (223 micrograms) than in women (201 micrograms); the dose significantly decreased with increasing age. The mean serum digoxin concentration was the same in men and women and it differed insignificantly between age groups, although older persons tended to have a higher concentration. The age - adjusted mean steady state digoxin concentration was 1.02 ng/ml in men and 0.98 ng/ml in women; in about 60% the concentration was within the "therapeutic" range (0.80-2.00 ng/ml). The concentrations were clearly related to daily dose of digoxin. At equal dose levels old persons tended to have higher concentrations than younger persons. The interindividual variation in serum digoxin concentrations was very wide. However, when digoxin measurements in the same subjects were repeated about three months later, a good correlation between the two measurements was found. The interval between the last dose of digoxin and the collection of blood (up to 41 h) had relatively little effect on individual serum digoxin concentrations. Patients on concomitant thiazide or loop diuretic therapy had the same mean serum digoxin concentration as those not-receiving a diuretic. The mean concentration was significantly higher in patients taking a thiazide or loop diuretic combined with triamterene. The difference may have been due to an interaction between triamterene and digoxin.

Clinical pharmacokinetics of amiodarone.

Amiodarone is an iodinated benzofuran derivative with recognised antiarrhythmic activity in man. As yet, its pharmacokinetic behaviour has not been satisfactorily characterised. Specific and sensitive high-pressure liquid chromatographic methods have become available only recently and this partly explains the scarcity of pharmacokinetic data on the drug. Available evidence suggests that absorption of amiodarone following oral administration is erratic and unpredictable; oral bioavailability ranges from 22 to 86%. The drug is eliminated largely by metabolism; less than 1% of the dose is excreted unchanged in the urine. Biliary excretion may have a role in the overall elimination of the drug. Desethyl-amiodarone is the only metabolite positively identified in the plasma of patients receiving treatment with amiodarone; no data are available on its possible pharmacological activity. Since it is a highly lipophilic drug, amiodarone is extensively distributed into tissues. Adipose tissue and skeletal muscle accumulate large amounts of the drug during long term treatment. Myocardium/plasma ratios of amiodarone are high both in man and in animals; peak concentrations in the myocardium are reached within half an hour after administration of an intravenous bolus to dogs. Placental transfer of amiodarone has been demonstrated in humans, while its blood profile is not modified by dialysis treatment. In vitro protein binding of amiodarone has been reported to be 96.3 +/- 0.6%. The plasma half-life of amiodarone after single-dose administration has been reported to be in the range of 3.2 to 79.7 hours. However, after withdrawal of long term amiodarone treatment the half-life is as long as 100 days. Total body clearance ranges from 0.10 to 0.77 L/min after single-dose intravenous administration, and the apparent volume of distribution ranges between 0.9 and 148 L/kg. Amiodarone disposition kinetics in patients with cardiac arrhythmias are not different from those in healthy volunteers. However, the possible effects of liver and cardiac failure on the drug's kinetics have not been studied. Amiodarone potentiates the anticoagulant effect of warfarin, probably by inhibition of its metabolism. Increases of steady-state concentrations of digoxin, together with the appearance of signs of digitalis toxicity, have been reported when amiodarone was given to patients receiving long term treatment with digoxin. Amiodarone has also been shown to interact with other antiarrhythmic agents such as quinidine and procainamide. The time of onset of action of amiodarone after a single intravenous dose ranges between 1 and 30 minutes and its duration of effect between 1 and 3 hours.(ABSTRACT TRUNCATED AT 400 WORDS)