Clinical study on digoxin tablets with high bioavailability (author's transl)

The relationship between different maintenance doses and the steady-state digoxin blood concentration was studied in 160 patients with heart failure. All patients received digoxin tablets of the same brand (Digacin). The bioavailability of this brand is 82% compared with an i.v. standard. During the treatment with daily doses of 0.2 mg and 0.3 mg average serum digoxin levels of 1.09 +/- 0.45 ng/ml and 1.33 +/- 0.53 ng/ml were measured in patients with normal renal function. The daily dose of 0.4 mg digoxin was in correlation to an average serum level of 1.75 +/- 0.81 ng/ml. 81% and 86% of all patients with normal renal function taking 0.2 or 0.3 mg digoxin every day were found to have levels in the range of 0.7 to 2.0 ng/ml. The influence of sex, age, height, body weight, maintenance dose, serum creatinine and serum potassium on the variance of the digoxin plasma levels was computed by multiple linear regression. The multiple correlation coefficient was r = 0.666, the coefficient of determination (100 r2) being 44.4%. Therefore 44.4% of the total variance could be explained by these variables. Individual variables accounted for the following percentages of the total variance: serum creatinine 29.1%; maintenance dose 14.5%; age 4.3%; and reciprocal of body weight 3.9%.     

341例地高辛血药浓度及影响因素分析

目的 对本院地高辛血药浓度结果进行分析,为临床安全、有效、合理使用该类药物提供参考.方法 分析本院2013年8月至2015年8月的341例地高辛血药浓度结果.结果 341例检测结果中,血药浓度＜ 0.8 ng/ml的有115例(33.72％),0.8～2.0 ng/ml的有183例(53.67％),＞2.0 ng/ml的有43例(12.61％).结论 临床药师需全面分析地高辛浓度的影响因素,提供个体化用药指导以促进临床合理用药.     

Serum digoxin and beta-methyldigoxin in elderly patients on hospital admission: correlation with home compliance and clinical variables

Summary Serum digoxin and beta-methyldigoxin (BMD) were measured in 165 elderly patients (age >60 years) admitted to hospital, of whom 109 had been treated at home with digoxin and 56 with BMD.The mean BMD level was significantly lower than that of digoxin (1.1 vs. 1.4 ng/ml). Creatinine clearance and daily dose were the variables most strongly associated with digoxin level, and the prescribed dose and serum albumin were the best predictors of the BMD concentration. Compliance was assessed by a compliance index (CI), namely the ratio of the measured glycoside concentration, corrected for creatinine clearance, over the expected steady-state dose, calculated from a hospitalized reference group. Compliant individuals in both treatment groups, i.e. those with a CI > the median value, were characterized by a lower daily dose and dosage frequency.Toxicity, whether clinical or electrocardiographic, was present in 9% of the patients and was associated only with a significantly higher mean serum level of the drug.     

Blood pressure response to conventional and low-dose enalapril in chronic renal failure

AIMS: In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat. METHODS: As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml(-1) (high) (n = 17) or below 10 ng ml(-1) (low) (n = 18), and the daily dose of enalapril titrated accordingly. RESULTS: Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min(-1) 1.73 m(2) in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5-10) and low (2.5-20) concentration group. At 3 months' follow-up, the dose was 10 (2.5-30) and 1.9 (1.25-5) mg (P < 0.0001), respectively. After 3 months median trough concentrations of enalaprilat were 82.5 (22-244) ng ml(-1) and 9.1 (2.5-74.8) ng ml(-1) (P < 0.002). At baseline the median systolic blood pressures in the two groups were 140 (110-200) and 133 (110-165), in the high and low enalaprilat concentration groups, respectively, and after 3 months they were 135 (105-170) and 130 (105-170) mmHg (NS). Median diastolic blood pressure was 80 mmHg in each group both at baseline (65-100) and at follow-up (60-95) (NS). There was no difference between the groups in concomitant antihypertensive treatment (number of patients treated, mean daily dose) during the observation period. Proteinuria remained stable during the study period in both groups; patients in the high concentration group had higher plasma potassium concentrations at day 90 and patients in the low group experienced a slight increase in GFR. CONCLUSIONS: In moderate to severe chronic renal insufficiency the same degree of blood pressure control was achieved on low as well as moderate daily doses of enalapril. This was irrespective of concomitant antihypertensive treatment.     

Digoxin compliance in patients from general practice.

1. Compliance with digoxin therapy has been assessed in a group of fifty patients receiving the drug in general practice but not attending hospital. 2. Compliance was estimated by comparing plasma digoxin concentrations before and after a 10 day period of measured digoxin consumption and by tablet counting. 3. Twelve patients had plasma concentrations which increased by more than 0.4 ng/ml during monitored intake and eight other patients took less than 80% of their tablets. These twenty patients were considered non-compliant. 4. A further three patients in whom plasma digoxin levels were zero when first seen but increased substantially during the run-in period were also adjudged non-compliant. 5. Non-compliance with prescribed digoxin dosage occurred, therefore, in 46% of the patients studied.     

婴儿口服地高辛醑剂后血药浓度监测结果分析

目的 探讨婴儿口服地高辛醑剂后血药浓度与临床疗效、给药剂量、合并用药情况、性别、年龄和体重的相关性.方法 查阅广东省人民医院2005 ～2009年口服地高辛醑剂的婴儿病历,记录疗效、用药情况、性别、体重、年龄、血药浓度监测结果等,用统计软件SPSS 13.0进行分析.结果 415例婴儿口服地高辛醑剂血药浓度测定值在治疗浓度0.8～2.2 ng/ml的共270例,占65.1％;低于治疗浓度范围下限(＜0.8 ng/ml)的共107例,占25.8％;高于治疗浓度范围上限(＞2.2 ng/ml)的共48例,占11.6％.婴儿地高辛血药浓度值与性别不存在明显相关性,但与给药剂量、年龄、体重、合并用药和具体病情有关.结论 地高辛血药浓度受个体因素与具体病情影响,药物剂量的制订和调整,应考虑可能影响地高辛血药浓度的各种因素,结合婴儿自身情况来决定最佳给药方案.     

Therapeutic thresholds in methadone maintenance treatment: a receiver operating characteristic analysis

Twenty-four-hour trough (R)- and (R,S)-methadone plasma concentrations were measured on 94 methadone maintenance treatment (MMT) patients classified as 'responders' or 'non-responders', based on urine toxicology evidence of recent illicit opiate use. Receiver operating characteristic (ROC) curves for daily dose, dose/bodyweight, and (R)- and (R,S)-methadone trough plasma concentrations were used to identify optimal thresholds; areas under the curve (AUC) were used to compare predictive power. Non-responders (n=37) had a lower mean dose (73 mg/day versus 147 mg/day; p<0.001), (R)-methadone concentration (136 ng/ml versus 223 ng/ml; p<0.005) and (R,S)-methadone concentration (266 ng/ml versus 409 ng/ml; p=0.001) than responders. On multivariate regression, duration of treatment and methadone dose were significantly associated with treatment response. After backward stepwise regression, each year of treatment increased the odds of abstinence from illicit opioid use by 34% (OR 1.34; 95% CI 1.14-1.57)); each 20mg of methadone dose by 36% (OR 1.36 CI; 95% CI 1.11-1.67). On ROC analysis, AUC for daily dose (0.77, 95% CI 0.68-0.87), dose/bodyweight (0.76, 95% CI 0.66-0.85), (R)-methadone (0.73, 95% CI 0.63-0.84) and (R,S)-methadone concentration (0.70, 95% CI 0.59-0.81) did not differ significantly. Dose/bodyweight, and trough plasma concentrations of (R)- or (R,S)-methadone were no better predictors of treatment response than daily dose, and did not improve the fit of the model for treatment outcome as judged by the likelihood ratio test (p=0.21, 0.88, and 0.97, respectively). Optimal therapeutic thresholds (sensitivity, specificity) were: daily dose 100mg/day (67%, 81%); (R)-methadone 200 ng/ml (51%, 78%); (R,S)-methadone 400 ng/ml (40%, 81%). Thresholds with specificity near 90% (dose 140 mg/day; (R)-methadone 250 ng/ml; (R,S)-methadone 500 ng/ml) may help guide dose titration for patients continuing to use illicit opiates.     

Improved sensitivity of digoxin assay by modification of the EMIT 2000 method

A modified EMIT 2000 digoxin assay was developed on the Cobas Mira plus analyzer for the determination of very low plasma concentrations of the drug. The major modifications were a higher plasma volume withdrawn during the analysis step and calibration curves constructed in the range 0-2 ng/ml using calibrators made up with biological matrix. Assays were controlled with an internal, four-level quality control (targets: 0.15; 0.60; 1.70; 2.70 ng/mL). The within-day and day-to-day mean observed values +/- SD (n = 10) of these quality controls were 0.14 +/- 0.02 and 0.15 +/- 0.02 ng/mL; 0.57 +/- 0.01 and 0.64 +/- 0.03 ng/mL; 1.55 +/- 0.06 and 1.62 +/- 0.04 ng/mL, 2.82 +/- 0.09 and 2.82 +/- 0.12 ng/mL, respectively. The detection and the quantification limits were 0.02 and 0.08 ng/mL, respectively. No significant difference was observed between digoxin plasma concentrations measured by the original and the modified EMIT 2000 digoxin assay in 25 plasma specimens, ranging from 0.4 to 3.0 ng/mL, from patients receiving the drug. This modified digoxin EMIT 2000 assay was subsequently used to study digoxin pharmacokinetics after each of 18 healthy volunteers was administered a single 0.5 mg oral dose. The pharmacokinetic parameters found in this study were in accordance with the literature in healthy subjects, using radioimmunoassay (RIA) for digoxin plasma concentration determinations. In conclusion, the lower limit of quantification of this modified EMIT 2000 digoxin assay is similar to that of RIA and can serve as a valuable screen for digoxin pharmacokinetic interactions studies.     

Interaction between digoxin and propafenone

The pharmacokinetic and pharmacodynamic interactions between digoxin and propafenone were investigated in 10 hospitalized patients with heart disease and cardiac arrhythmias. During steady state (0.25 mg/day) the glycoside was combined with 600 mg of propafenone daily for 1 week. The mean +/- SD serum digoxin concentration (SDC) was 0.97 +/- 0.29 ng/ml before and 1.54 +/- 0.65 ng/ml (p less than 0.003) during propafenone administration. Propafenone induced a mean decrease in 31.1 and 31.7% in total and renal digoxin clearances, respectively. The increase in SDCs was accompanied by a decrease in heart rate (HR) and shortening of QTC (QT interval corrected for HR). In patients receiving digoxin and propafenone simultaneously, the SDCs should be monitored and the digoxin dose reduced if there is evidence of toxicity.     

Effect of digoxin on the sensitivity to flickering light.

1 The sensitivity to flickering light at various light frequencies (DeLange curve) was determined in 20 controls and 45 patients receiving maintenance doses of digoxin. 2 Flicker thresholds (mean percentage of maximal light modulation +/- s.d.; F 30 Hz) were 7.6 +/- 1.7 in controls and 9.4 +/- 1.7 in patients with optimal plasma digoxin levels (0.5-1.9 ng/ml), but they rose to 15.5 +/- 1.9 at subtoxic levels (2.0-3.0 ng/ml), and to 21.8 +/- 2.6 at toxic levels (above 3.0 ng/ml). 3 Flicker sensitivity was inversely correlated with plasma digoxin levels and returned to baseline values when the administration of digoxin was interrupted. 4 The DeLange curve seems to be a valuable tool to measure the toxic effects of digitalis on the visual system.     

The hemodynamic and pharmacokinetic interactions between chronic use of oral levosimendan and digoxin in patients with NYHA Classes II-III heart failure

OBJECTIVE: Levosimendan is a calcium-sensitizing drug for the treatment of heart failure. The aim of this exploratory study was to assess the hemodynamic and pharmacokinetic interactions between digoxin and oral levosimendan as well as the proarrhythmic potential of this combination in patients with chronic heart failure. MATERIALS: Male or female patients (n = 24) with chronic heart failure of NYHA Classes II-III. METHODS: A randomized, placebo-controlled, double-blind, parallel-group trial. After a 1-week digoxin-free washout period, the patients were randomized to receive either digoxin and levosimendan (digoxin + levosimendan), or digoxin and placebo (digoxin) orally for 14 +/- 2 days. The levosimendan dose was 1 mg 3 times daily, and the digoxin dose was 0.125-0.25 mg once daily. Systolic time intervals, electrocardiography (ECG), magneto-cardiography (MCG) and 24-h ambulatory ECG were performed at baseline and at the end of each treatment period. Pharmacokinetic variables of levosimendan and digoxin were calculated in both treatment periods. Steady-state concentrations of the active metabolites OR-1855 and OR-1896 were determined at baseline at Visit 2. RESULTS: There tended to be a greater shortening of QS2i (suggesting trend to positive inotropy) in the digoxin + levosimendan group (-14ms) compared with the digoxin group (-5ms), although the difference was not statistically significant (p=0.359). However, the change from baseline in QS2i after digoxin + levosimendan was of statistically borderline significance (p=0.05). The change from baseline in the digoxin group was not statistically significant. ECG and MCG repolarization measures and occurrence of nonsustained ventricular tachycardia showed no substantial differences. After 2 weeks of digoxin + levosimendan treatment, mean area under the curve (AUC) of levosimendan increased approximately by 49% (p<0.01). The maximum plasma concentration (Cmax) of levosimendan increased from 17 to 23 ng/ml. The mean concentrations of the metabolites OR-1855 and OR-1896 in plasma were 4.3 and 8.3 ng/ml, respectively. CONCLUSIONS: The addition of oral levosimendan to digoxin therapy produced only a modest statistically nonsignificant additive inotropic effect. In contrast to the earlier data with intravenous levosimendan, the results indicate a pharmacokinetic interaction between levosimendan and digoxin. Data obtained from repolarization analyses and ambulatory ECG did not indicate any possible proarrhythmic effects of the combination.     

Serum digoxin concentrations in a representative digoxin — Consuming adult population

Summary 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 µg) than in women (201 µg); 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.     

Fluphenazine pharmacokinetics and therapeutic response

We conducted a double-blind study of therapeutic outcome versus mean steady-state levels in 29 newly admitted schizophrenic and schizoaffective patients who were treated with a constant dose of fluphenazine HCl over a 2-week period. Both an upper and lower end of the therapeutic window were suggested by three nonresponders whose plasma levels were above 2.8 ng per ml and by two nonresponders and one partial responder whose plasma levels were below 0.2 ng per ml. The mean terminal half-life of fluphenazine (±SD) was 16.4±13.3 h. We found that concomitant use of benztropin mesylate during the initial 4 weeks of fluphenazine treatment did not significantly alter fluphenazine plasma levels.     

Single and chronic dose pharmacokinetic studies of sodium valproate in epileptic patients

Summary In four refractory epileptic patients, peak plasma levels of sodium valproate occurred within 1.5 to 3 h after a single oral dose of valproate and the decline in plasma levels followed a monoexponential course with a t_1/2 of 11.4 ± 0.1 h. The mean value for apparent volume of distribution was 0.176 ± 0.013 l/kg and for total plasma clearance 0.0106 ± 0.0009 l/h/kg. Steady state plasma levels were predicted using the method of superposition utilizing pharmacokinetic parameters determined following a single dose of valproate and were 78–123% of the predicted values for two patients receiving valproate alone, and 37–64% of the predicted values for the two patients receiving carbamazepine in addition to valproate. In a further group of 20 patients the mean daily doses of valproate for 8 patients receiving valproate alone (25.4 ± 4.9 mg/kg) was significantly less than those for the 12 patients receiving concomitant anticonvulsant therapy (41.6 ± 12.3 mg/kg) (p<0.005). In addition, the steady state predose plasma levels of valproate were significantly higher in the valproate alone patients (90.3 ± 8.7 µg/ml) compared to the patients receiving additional anticonvulsants (75.3 ± 13.8 µg/ml) (p<0.01). The higher dose requirements of valproate and lower predose and steady state plasma levels for those patients on multiple anticonvulsants indicate an interaction between valproate and other anticonvulsants.     

Digoxin-interactions in man: Spironolactone reduces renal but not biliary digoxin clearance

Summary The possibility of an inhibitory effect of spironolactone on the biliary clearance of digoxin has been investigated in 6 healthy subjects.Plasma clearance and the renal and biliary clearance of digoxin were determined twice at steady state (digoxin 0.5 to 1 mg·d^–1 p.o. for 6 days), alone or in combination with spironolactone 200 mg daily, after an intravenous dose of digoxin (0.7 × oral dose) on Day 7. Plasma and urine were collected for 48 h. Biliary clearance of digoxin was determined on Day 8 by a duodenal perfusion technique.During spironolactone treatment plasma digoxin clearance tended to be lower (255 vs 224 ml/min; P=0.057) and renal clearance significantly lower (166 vs 144 ml/min), while the biliary clearance of digoxin remained unchanged (106 vs 103 ml/min).Thus, spironolactone reduced the renal clearance of digoxin by an average of 13%, without affecting its biliary clearance.     

Poor correlation between predicted ideal and prescribed digoxin dose: a community‐based pharmacokinetic study in the elderly

□ This study assessed if population‐based pharmacokinetics predicted measured plasma digoxin concentrations in elderly community‐managed patients □ Twenty‐seven per cent of the sample showed plasma concentrations consistent with a therapeutic level over an entire 24‐hour dosing schedule; 36 per cent showed therapeutic levels for at least some of the dosing schedule; the remainder showed digoxin concentrations not consistent with achieving a therapeutic plasma concentration for any part of the dosing schedule □ The mean daily prescribed dose of digoxin was significantly lower than that predicted from population kinetics.     

Plasma digoxin concentration fluctuations associated with timing of plasma sampling and amiodarone administration

A 31-year-old man with dilated cardiomyopathy was hospitalized for new-onset atrial fibrillation. Oral amiodarone 600 mg/day was started to control his arrhythmia, and the patient continued to receive digoxin 0.125 mg/day, which was prescribed 4 days earlier at a heart failure clinic. The patient's digoxin plasma concentration peaked early on hospital day 3 at 2.93 ng/ml; digoxin was withheld. Over the next 3 days, the patient's digoxin plasma concentrations rose and fell daily. These fluctuations correlated with the timing of blood sampling in relation to oral amiodarone administration. The patient's renal function remained stable, and he developed no signs or symptoms of digoxin toxicity. To our knowledge, no case reports have associated significant fluctuations of digoxin plasma concentrations that correspond to the timing of oral amiodarone administration. Tissue-to-plasma redistribution appears to be a possible mechanism for this interaction, with the most significant effect occurring 8-10 hours after amiodarone administration. Clinicians should be aware that digoxin plasma concentrations may not correlate with digoxin tissue concentrations in this setting. When a loading dose of oral amiodarone is required in a patient receiving digoxin, the digoxin dosage should first be reduced, and digoxin therapy should be adjusted based on signs and symptoms of digoxin toxicity.     

Interindividual differences in chlorthalidone concentration in plasma and red cells of man after single and multiple doses

Summary A gas chromatographic method has been employed to determine chlorthalidone in plasma and whole blood after therapeutic doses. Radioactively labelled chlorthalidone was used for in vitro studies of the uptake of chlorthalidone from plasma by red blood cells. Chlorthalidone was markedly concentrated in red cells and as a compartment they would account for at least 30% of total drug in the body after multiple doses. The ratio between the plasma and red cell concentration of chlorthalidone varied between individuals. After a single oral dose of 50 mg in 6 healthy volunteers chlorthalidone was eliminated with a half-life of 51 to 89 hours. The apparent volume of distribution varied between 3 and 13 1/kg and the clearance between 53 and 145 ml/min. The mean steady-state plasma concentrations during treatment with a standard dose of 50 mg daily (n=10) varied 5-fold between individuals. During the steady state approximately 50% of the daily dose was excreted unchanged in the urine during 24 hrs. The plasma levels observed in patients were higher than those predicted from the single oral dose studies in healthy volunteers.A preliminary report of this paper was presented at the Ann. Meet. Sw. Med. Soc. Nov. 1973Supported by a Geigy scholarship     

Radioimmunoassay of digoxin in serum using monoclonal antibodies and assessment of interference by digoxin-like immunoreactive substances

We used 7 monoclonal antibodies (MoAbs) and one polyclonal antibody to develop radioimmunoassays (RIAs) for digoxin in serum or plasma. These RIAs were tested for measuring apparent digoxin concentrations in serum from patients receiving the drug, from normal individuals, and in cord blood plasma. We found that two MoAbs cross-reacted significantly with substances in cord blood. The magnitude of cross-reactivity was dependent on the incubation time and temperature. Under equilibrium conditions, one antibody gave apparent digoxin values in cord blood plasma averaging 2.15 ng/ml. We suggest that this cross-reactivity is partially due to progesterone and 17-hydroxyprogesterone in cord blood plasma. The antibody that shows high cross-reactivity with digoxin-like immunoreactive substances may prove a useful tool for studies dealing with characterization of the cross-reacting compounds.