Dose Of Digoxin Research Articles

The effect of digoxin-specific active immunization on digoxin toxicity and distribution in the guinea-pig.

In guinea-pigs intravenously infused with digoxin, prior immunization using a digoxin-human serum albumin conjugate increased by 3- and 2.4-fold, respectively, the digoxin doses causing the first signs of cardiotoxicity and death. At death, serum digoxin concentration was four times higher in immunized than in control animals. In the immunized guinea-pigs 50% of the serum digoxin was protein bound, presumably mainly to digoxin-specific antibodies, since in the controls the bound fraction was only 1-2%. Generally, tissue digoxin concentrations were not increased to the same extent as the lethal dose, and in the heart and lungs the increase was not significant. With cardiac (ventricle) subcellular fractions, there was no difference between control and immunized animals in the digoxin concentration of the 'microsomal' pellet. This subfraction contains the plasma membrane and the associated sodium pumps which are considered to be the sites at which the pharmacologically active digoxin binds. It seems likely, therefore, that the greater digoxin resistance in the immunized animals can be explained on the basis of reduced drug access to the site of action within the heart.

Distribution of Maintenance Doses of Digoxin Required to Produce Therapeutic Serum Concentrations in Elderly Patients

Distribution of Maintenance Doses of Digoxin Required to Produce Therapeutic Serum Concentrations in Elderly Patients

Amiodarone does not affect digoxin kinetics in the rabbit.

It has been reported that amiodarone may interact with digoxin in man. We investigated the effects of amiodarone pretreatment (35 mg kg-1 day-1) on the pharmacokinetics of a single dose of digoxin (50 micrograms kg-1) in 6 rabbits. Total body clearance of digoxin was 138.84 +/- 44.67 and 147.99 +/- 29.17 ml min-1, serum half life 187.9 +/- 60.9 and 181.34 +/- 25.57 min and volume of distribution 35.4 +/- 8.54 and 37.8 +/- 3.9 litres before and after amiodarone treatment, respectively. None of these changes were statistically significant. We conclude that the presence of an amiodarone-induced change in digoxin pharmacokinetics in the rabbit was not evident and that other animal models will be necessary for studying this interaction.

Effects of AN-132 and quinidine, antiarrhythmic agents, on plasma digoxin concentrations in rats.

The effects of AN-132, 3-(diisopropylaminoethyl-amino)-2',6'-dimethylpropionanilide.2H 3PO4, on chloroform-induced arrhythmias and plasma digoxin concentrations have been compared with those of quinidine in rats. AN-132 (0.01-3 mg kg-1) administered orally significantly inhibited the incidence of cardiac arrhythmias in a dose-related fashion. A single dose of digoxin (1 mg kg-1) given orally for 7 consecutive days was followed, on day 8, orally by digoxin alone, or together with AN-132 (50, 100 and 200 mg kg-1) or quinidine (25 and 50 mg kg-1). The AUC0-24 and Cmax of plasma digoxin were enhanced significantly by co-administration of quinidine, but not by AN-132.

Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers

The aim of this study was to investigate whether multiple doses of the oral and highly selective dipeptidyl peptidase-4 inhibitor linagliptin affect the steady-state pharmacokinetics of the P-glycoprotein substrate digoxin. This single-center, open-label, two-period cross-over study involved healthy subjects (n=20), randomized to treatment sequence AB or BA, where A comprised 0.25mg digoxin qd for 5days, then 0.25mg digoxin qd plus 5mg linagliptin qd for 6days, and B comprised 0.25mg digoxin qd for 11days. A treatment-free period (≥35days for AB and 14days for BA) separated each treatment in both sequences. There were no clinically significant changes in steady-state pharmacokinetic parameters of digoxin when it was co-administered with linagliptin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUC(τ,ss), C (max,ss) and renal clearance (CL( R,0-24,ss)) of digoxin were all within the bioequivalence range 80-125%, which is important as digoxin has a narrow therapeutic range. There was a low incidence of adverse events, which were randomly distributed between treatment groups. In conclusion, linagliptin did not alter the pharmacokinetics of digoxin in this study, indicating that linagliptin does not inhibit P-glycoprotein or other transporters relevant for digoxin pharmacokinetics. These results suggest that linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated.

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

Abstract Focal points

Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC)

Phase II trial of second-line erlotinib and digoxin for nonsmall cell lung cancer (NSCLC) Fadi Kayali, Muhamad A Janjua, Damian A Laber, Donald Miller, Goetz H KloeckerUniversity of Louisville, James Graham Brown Cancer Center, Louisville, KY, USABackground: In vitro digoxin sensitizes cancer cells to the induction of apoptosis by chemotherapy. Inhibition of the Na/K-ATPase enzyme by ouabain disturbs the intracellular ion composition of cancer cells, altering cellular homeostasis. This suggests that inhibition of the Na/K pump results in cellular sensitization of malignant but not benign cells to the induction of apoptosis. Epidemiologic studies have also shown beneficial effects of digitalis in breast cancer incidence. At ASCO (American Society of Clinical Oncology) 2007 our group presented a Phase II study showing encouraging results by adding digoxin to biochemotherapy for melanoma. Erlotinib is one of the standard second-line treatments for nonsmall cell lung cancer (NSCLC), with a response rate (RR) of 10%. This study's hypothesis was that adding digoxin to erlotinib will improve the RR and time to progression (TTP) in NSCLC.Methods: Patients with progressive disease (PD) after chemotherapy were enrolled if they had an ECOG (Eastern Cooperative Oncology Group) score from 0 to 2 and good organ function. Daily erlotinib 150 mg and digoxin 0.25 mg were taken by mouth. The digoxin dose was adjusted to keep levels between 1 and 2 ng/mL. Computed tomography scans were done every 6 weeks. Treatment continued until PD or significant toxicity occurred.Results: Patient accrual lasted from March 2006 until August 2008 and was stopped early at the time of interim analysis. Twenty-eight patients were enrolled, and 24 who completed at least 6 weeks of therapy are presented here. All patients had unresectable NSCLC stage III/IV at diagnosis. Median age was 61 (34–78), 14 were female, 17 had prior radiation (not involving the target lesions), 23 had one prior chemotherapy, and one subject had two. Only one patient was a never-smoker. Histologies were 50% adenocarcinoma, 30% squamous, and 20% unspecified. One patient had a partial response, nine had stable disease, and 14 had progressive disease. The median TTP was 61 days (9–366) and median survival 157 days (9–844). Side effects were similar to erlotinib single agent with no treatment-related mortality. There were no unexpected or increased adverse events related to digoxin.Conclusions: Digoxin did not increase the response rate of erlotinib in the treatment of progressive NSCLC. The TTP and survival seen in this study were similar to the published results with erlotinib alone. This combination does not warrant further clinical studies in NSCLC.Keywords: metastatic lung cancer treatment, digitalis, erlotinib

DIGOXIN DOSE EVALUATION ON HEART FAILURE PATIENTS WITH RENAL DISFUNCTION IN RSUP DR. SARDJITO, YOGYAKARTA

Digoxin is a medicine with narrow therapeutic index. Digoxin is widely used for heart failure treatment. Adjustment of digoxin dose is needed in patient with renal dysfunction. This research were done to evaluate digoxin dose in heart failure patient with renal dysfunction. This research was retrospective and prospective research, performed in Dr. Sardjito hospital during January 2010 to March 2011. Data were collected from patient medical record and then evaluated with descriptive method. From 43 patients, percentage men compare to women were 56 % : 44 %. Most patients come from age of 50 – 59 (34.88%). Dose calculation based on pharmacokinetic concept found that some of digoxin dose in patients were exceed digoxin therapeutic concentration. From 19 women patients there were 11 patients use digoxin dose exceed digoxin therapeutic concentration when calculate by pharmacokinetic while from 24 men patients there were 14 patients use digoxin dose exceed digoxin therapeutic concentration when calculate by pharmacokinetic. Dose recalculation method was mostly based on literature data particularly for pharmacokinetic parameter values i.e. volume distribution, half life, and clearance. Therefore, the corrected doses suggested in this thesis should be regarded as theoretical estimates. Furthermore, it was also found that patients did not get appropriate loading dose of digoxin. However, drug dosing for digoxin were individual dose, therefore overall found that patient clinical outcome was generally better. Keywords : digoxin, heart failure, renal dysfunction, clinical outcome

Effects of Multiple Doses of Ambrisentan on the Pharmacokinetics of a Single Dose of Digoxin in Healthy Volunteers

Effects of Multiple Doses of Ambrisentan on the Pharmacokinetics of a Single Dose of Digoxin in Healthy Volunteers

Individual dosage of digoxin in patients with heart failure

After the publication of DIG trial, the therapeutic target of serum digoxin concentration (SDC) for the treatment of heart failure (HF) has been lowered (0.40-1.00 ng/ml). However, the majority of equations to calculate digoxin dosages were developed for higher SDCs. Recently, a new equation was validated in Asian population for low SDCs by Konishi et al., but results in Caucasians are unknown. This study was aimed to test the Konishi equation in Caucasians specifically targeting low SDCs. Furthermore, the Konishi equation was compared with other frequently used equations. This was a prospective, multicenter study. Clinically indicated digoxin was given in 40 HF patients. The dosage was calculated with the Konishi equation. The SDC was measured at 1 and 6 months after starting digoxin. Adherence to digoxin was monitored with a specific questionnaire. After exclusion of patients admitting poor adherence, we found a reasonable correlation between predicted and measured SDC (r=0.48; P<0.01) by the Konishi equation. Excluding patients with poor adherence and relevant worsening of renal function, the measured SDC (n=54 measurements) was within the pre-defined therapeutic range in 95% of the cases. The mean, maximal and minimal measured SDC were 0.69±0.19, 1.00 and 0.32 ng/ml, respectively. The correlation was weaker for the Jelliffe, the Koup and Jusko, and the Bauman equations. This study supports the clinical validity of the Konishi equation for calculating individual digoxin dosage in Caucasians, targeting SDCs according to current HF guidelines.

Digoxin

Digoxin

An Improved Nonlinear Model Describing the Hepatic Pharmacokinetics of Digoxin: Evidence for Two Functionally Different Uptake Systems and Saturable Binding

To develop a semi-distributed liver model for the evaluation of saturable sinusoidal uptake and binding kinetics of the Oatp1a4 substrate digoxin. In the perfused rat liver, two successive digoxin doses of 42 and 125 microg were administered, and the outflow concentration was determined by LC/MS/MS. [14C]-sucrose was used as vascular reference. The data were analyzed simultaneously by a population approach using sucrose to determine the sinusoidal mixing of digoxin. The results suggest the existence of a high-affinity, low-capacity system, and a low-affinity, high-capacity system for sinusoidal uptake with apparent Michaelis constants (K(M)) of 0.24 and 332 microg/ml, respectively. Incorporation of saturable sinusoidal binding of digoxin considerably improved the fit, and the parameter estimates were consistent with those of binding to hepatic Na,K-ATPase. Simpler models that neglect the concentration gradient in flow direction failed to describe the outflow data in the high dose range. The semi-distributed liver model with saturable uptake should be useful for a functional characterization of transporters in the in situ rat liver.

Effects of Laropiprant, a Selective Prostaglandin D2 Receptor 1 Antagonist, on the Steady‐State Pharmacokinetics of Digoxin in Healthy Adult Subjects

Laropiprant, a prostaglandin D(2) receptor-1 antagonist shown to reduce flushing symptoms, has been combined with niacin for treatment of dyslipidemia. This open-label, randomized, 2-period crossover study assessed the effects of laropiprant on the pharmacokinetics of digoxin, with 13 healthy subjects randomized to 2 treatments administered in random order with a 10-day or longer washout period: (A) single-dose digoxin 0.5 mg on day 1 and once-daily oral doses of laropiprant 40 mg for 10 days beginning 5 days prior to digoxin dosing (day -5 to day 5); (B) single-dose digoxin 0.5 mg on day 1. Blood was collected over the course of 120 hours post digoxin dose to assess pharmacokinetics of immunoreactive digoxin. Comparability was declared if the 90% confidence interval for the geometric mean ratio of laropiprant+digoxin to digoxin alone of the area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) for immunoreactive digoxin fell within 0.80 to 1.25. The AUC(0-infinity) and maximum observed plasma concentration (C(max)) geometric mean ratios of immunoreactive digoxin were 0.91 (90% confidence interval, 0.76-1.10) and 1.04 (90% confidence interval, 0.91-1.21), respectively. Median time of occurrence of C(max) and mean half-life of immunoreactive digoxin were comparable in the presence and absence of laropiprant. Coadministration of digoxin and laropiprant was generally well tolerated. The small decrease in exposure to immunoreactive digoxin (approximately 10%) following coadministration of laropiprant and digoxin is not considered to be clinically meaningful.

Landmark Publication from The American Journal of the Medical Sciences: The Clinical Pharmacology of Digitalis Glycosides: A Review

The metabolic half-times and excretion rates of labeled cardiac glycosides are related to pharmacologic or therapeutic activity. Digoxin, a short-acting glycoside, is excreted primarily in the urine and has a serum half-time of 34hours. This function is related primarily to digoxin excretion. Digitoxin, a long-acting glycoside, has a serum half-time of 50+ hours and a physiologic half-time of 51/2 days. It is excreted primarily in the urine as metabolites of the parent compound. Renal failure compromises digoxin excretion and prolongs the digoxin serum half-time and thereby the pharmacologic activity of the drug. As excretion is related to creatinine clearance, dosage should be reduced in proportion to reduction in creatinine clearance in renal insufficiency. Hyper-thyroid patients have lower digoxin serum levels and hypothyroid patients higher digoxin serum levels when compared to euthyroid patients. This finding confirms the clinical impression of digitalis resistance in hyperthyoidism and sensitivity in myxe-dema. Appropriate alterations in digoxin dosage in thyroid disease are justified. Patients with liver disease and cor pulmonale have normal digoxin serum levels, half-times and excretion rates. Increased digitalis sensitivity in these patients is related to other factors. Knowledge of the serum half-time, route of excretion, and rate of excretion of the cardiac glycosides is now available. Application of this information to the patient receiving digitalis assists in avoiding over- and under-digitalization—both common clinical problems. If doubt exists regarding digitalis dosage, smaller, rather than larger, doses are suggested to avoid toxicity.

Interactions between Verapamil and Digoxin in Langendorff‐Perfused Rat Hearts: The Role of Inhibition of P‐glycoprotein in the Heart

P-glycoprotein (P-gp) is expressed in tumour cells as well as normal tissues including heart. Modulation of P-gp transport in vivo may lead to increased drug penetrance to tissues with resulting increases in toxicity. We aimed to investigate the effects of P-gp on the isolated heart by digoxin infusion in the absence and presence of verapamil. The study was performed in Langendorff isolated perfused rat hearts. After a 20 min. stabilisation period with Tyrode Buffer, digoxin (125 μg/5 mL) was infused for 10 min. in the control group (n = 7). The same dose of digoxin was infused during perfusion with verapamil (1 nm) containing Tyrode Buffer (n = 8) in the study group. Outflow concentration and cardiac parameters of digoxin were measured at frequent intervals for 40 min. AUEC((0-40 min)) for left ventricular developed pressure was significantly increased in the presence of verapamil (4260 ± 39.37 mmHg min versus 4607 ± 98.09 mmHg min; 95% CI -587.7 to -105.8; p = 0.0083). The significant increases in left ventricular developed pressure were at 20, 25, 30, 35 and 40 min. AUC((0-40 min)) value for outflow digoxin concentration-time curve was significantly lower in the presence of verapamil. Verapamil increased the positive inotropic effect of digoxin, probably through the inhibition of P-gp, which effluxes digoxin out of cardiac cells.

Clinical Repercussions of Analytical Interferences Due to Aldosterone Antagonists in Digoxin Immunoassays: An Assessment

Analytical interferences in digoxin immunoassays constitute a well-known problem, with repercussions for therapeutic drug monitoring. Clinically effective doses of spironolactone and potassium canrenoate cross-react in several digoxin immunoassays, producing falsely elevated or lowered concentrations. This study evaluates the interferences caused by these drugs in the microparticle enzyme immunoassay (MEIA III) in comparison with another 3 immunoassays used for digoxin therapeutic drug monitoring: MEIA II, fluorescence polarization immunoassay, and enzyme multiplied immunoassay. The potential clinical implications of assay discrepancies in patient care are also assessed. To evaluate assay performance, in vitro specimens and real patient samples were measured using the 4 assays. Five serum pools were spiked with digoxin to achieve concentrations of 1 and 2.25 ng/mL digoxin and measured with the immunoassays before and after supplementation. Real samples from patients receiving digoxin (n = 39), digoxin and spironolactone (n = 35), or digoxin and potassium canrenoate (n = 4) were also quantified. The influence of ultrafiltration was evaluated in 3 pools from 29 additional patients. The implications of assay discrepancies for dose recommendations were also evaluated. In general, the results obtained for the in vitro and in vivo approaches coincided, confirming statistically significant differences in the assays regardless of the type of sample. MEIA III showed positive interference against the well-known negative interference attributed to MEIA II. According to Bland-Altman analysis, it is not possible to assume the interchangeability of the immunoassays evaluated. Thus, individual patients must be monitored with the same technique even in the absence of potential interferences. Discordant digoxin dose recommendations were estimated in 31% of patients not treated with interfering drugs and in 43% of cotreated patients. From a clinical perspective, analytical interferences in digoxin immunoassays are a real and frequent problem, which seems even more important in view of the lower therapeutic range now recommended.

The Effects of Pregnenolone 16α-Carbonitrile Dosing on Digoxin Pharmacokinetics and Intestinal Absorption in the Rat.

The effect of Pgp induction in rats by pregnenolone 16α-carbonitrile (PCN) (3 days, 35 mg/kg/d, p.o.) on digoxin pharmacokinetics and intestinal transport has been assessed. After intravenous or oral digoxin dosing the arterial and hepatic portal vein (oral) AUC(0-24h) were significantly reduced by PCN pre-treatment. Biliary digoxin clearance increased 2-fold following PCN treatment. PCN significantly increased net digoxin secretion (2.05- and 4.5-fold respectively) in ileum and colon but not in duodenum or jejunum. This increased secretion correlated with increased Pgp protein expression in ileum and colon. Both intestinal and biliary excretion therefore contribute to altered digoxin disposition following PCN.

Effect of saquinavir/ritonavir on P-glycoprotein activity in healthy volunteers using digoxin as a probe

Saquinavir and ritonavir, both human immunodeficiency virus-1 protease inhibitors, also inhibit the adenosine triphosphate-dependent efflux pump P-glycoprotein (P-gp), which is located at a variety of anatomic sites, including the human intestine. P-gp plays an important role in the absorption, distribution and elimination of numerous drugs. This study investigated the inhibitory potential of multiple administrations of ritonavir-boosted saquinavir at the target therapeutic dose of 1,000 mg saquinavir/100 mg ritonavir twice daily on the pharmacokinetics of oral digoxin, a model P-gp substrate that is predominantly excreted as unchanged drug in the urine. In an open-label, 1-sequence, 2-period crossover study, a single digoxin dose of 0.5 mg was administered orally on Day 1. From Days 11 through 26, participants received oral administration of saquinavir/ritonavir 1,000/100 mg twice daily. A second dose of digoxin was administered on Day 24. Blood and urine sampling for pharmacokinetic analyses of digoxin was performed at scheduled time points on Days 1 - 4 and Days 24 - 27. Serial blood samples were drawn to determine plasma levels of saquinavir and ritonavir on Days 21 - 24. Adverse event reports were collected. Of the 17 enrolled participants (9 males and 8 females) who received at least one dose of study medication, 16 completed the study. Two weeks of pretreatment with ritonavir and saquinavir resulted in a 1.27-fold increase in digoxin Cmax (90% confidence interval (1.05 - 1.54)) and a 1.49-fold increase in AUC0-72 (90% CI (1.32 - 1.69)). Renal clearance decreased by a factor 0.88 from 111 to 97.3 ml/min while digoxin half-life increased from 37.0 to 45.3 h. The unbound fraction of digoxin was almost unaffected. The changes in digoxin renal clearance and exposure (AUC0-72) following 2 weeks of treatment with saquinavir/ritonavir were found to be more pronounced among female participants compared with males. Plasma concentrations of saquinavir/ritonavir at trough and at 4 h postdose were within the expected ranges for each gender, with female participants showing higher concentrations than male participants. All three treatments were well tolerated, with no serious adverse events noted. Despite the higher digoxin exposure among females compared to males following saquinavir/ritonavir administration, overall safety profiles were similar. On electrocardiographic readings, a trend of a longer PR interval was noted with triple combination of agents. Pretreatment with saquinavir/ritonavir 1,000/100 mg twice daily increased digoxin exposure most likely via P-gp-inhibition. Given the relatively narrow therapeutic window of digoxin, caution should be exercised when these three drugs are administered together. It is recommended to reduce digoxin doses and to monitor digoxin serum concentrations.

Optimisation of Digoxin Maintenance Dose in Toxicity

ABSTRACTBackgroundDigoxin pharmacokinetics can be altered by disease states, age‐related decline in renal function, decreased skeletal muscle mass and drug interactions.AimTo report a case of digoxin toxicity in a patient with advanced congestive heart failure in atrial fibrillation and worsening renal failure; and to describe the application of pharmacokinetic principles in the optimisation of digoxin dosing.Clinical detailsA 59‐year‐old Caucasian male presented with a week long history of abdominal pain, increased dyspnoea and lethargy. His medical history included heart failure, atrial fibrillation, hypertension, ischaemic heart disease, type 2 diabetes, acute on chronic renal failure, dyslipidaemia, anaemia and morbid obesity. His serum biochemistry revealed hyperkalaemia of 6.9 mmol/L, elevated creatinine of 407 μmol/L (prior baseline 247 μmol/L) and a trough serum digoxin concentration of 3.4 nmol/L at steady state on an oral maintenance digoxin dose of 125 microgram daily. His calcium and magnesium levels were in the normal range.OutcomesHyperkalaemia was corrected and the potassium‐sparing medications, spironolactone and perindopril, were withheld. Digoxin was withheld until digoxin's serum concentration returned to the therapeutic range. A reduced maintenance dose of digoxin 62.5 microgram on alternate days was calculated and recommended by the clinical pharmacist. At discharge, the patient felt significantly better and was able to engage with activities of daily living. Perindopril and spironolactone were recommenced once the potassium had returned to normal levels. The patient was unaware of signs and symptoms of digoxin toxicity and the clinical pharmacist provided counselling prior to discharge. The patient's local doctor was requested to closely monitor his renal function and potassium levels and to check his trough serum digoxin concentration if toxicity was suspected.ConclusionPharmacists and clinicians need to understand digoxin's pharmacokinetics in various clinical settings to be able to make appropriate dose adjustments.

Massive ingestion of cardiac drugs: toxicokinetic aspects of digoxin and sotalol during hemofiltration

Case. We present the case of a 75-year-old patient admitted to the emergency department after ingesting a large amount of several cardiac drugs, among which were digoxin and sotalol. Because of renal insufficiency, cardiogenic shock, and high serum digoxin levels, the patient received continuous venovenous hemofiltration (CVVH) and digoxin-specific Fab fragments. Digoxin and the digoxin-specific Fab fragments are normally cleared by the kidneys. Methods. Serum-free and total digoxin and serum sotalol concentrations were monitored for several days. Results. Less than 10% of the estimated ingested dose of digoxin was cleared by CVVH within 5 days. Conclusion. CVVH has little influence on the clearance of Fab-bound digoxin from the body. In contrast, sotalol is efficiently cleared by CVVH.