He has been in a nursing home for 2 years now and receives digoxin 0. Clinical pharmacokinetics of digitoxin university of arizona. Population pharmacokinetic analysis of digoxin in chinese. In addition to the renal clearance of creatinine, the bioavailability of the digoxin formulation used, the volume of distribution, the amount of extrarenal clearance, body weight and serum albumin concentration, are other factors which may modify the serum level of digoxin. The degree of binding to serum albumin is 20 to 30%. The pharmacodynamic effects of digoxin, including toxic symptoms, are correlated with the uptake of digoxin in the heart after a single dose and with the steady state serum digoxin concentration during maintenance therapy. Renal clearance of digoxin exceeds the glomerular filtration rate of its free fraction, thus indicating a tubular secretion component. The substances of interest include any chemical xenobiotic such as. Sep 26, 2018 digoxin oral tablet is a prescription medication thats used to treat atrial fibrillation an irregular heart rhythm and heart failure. Pharmacokinetic and pharmacodynamic drug interactions between digoxin and macrogol 4000, a laxative polymer, in healthy volunteers. Understanding steady state pharmacokinetics certara. Describe the bloavailability, volume of distribution, protein binding, elimination pathways and clinical effects of digoxin. Massachusetts digoxin, the cardiac glycoside most frequently used in clinical practice in the united states, can be given orally or intravenously and has an excretory halflife of 36 to 48 hours in patients with serum creatinine and blood urea nitrogen values in the normal.
Digoxin pharmacokinetics were studied in a pediatric population with an age range of 6 days to 1 year using the population pharmacokinetic approach. Oct 20, 1973 three subjects were first given a digoxin tablet in the fasting state and subsequently received the same formulation in the fed state, to simulate a spurious oral bioavailability difference. The discrepancy between the plasma and urine halflives was even more marked when randomly labelled 3h digoxin was used. There is only one study that has examined the relative bioavailability of two commercial. Absorption of digoxin from digoxin tablets has been demonstrated to be 60% to 80% complete compared to an identical intravenous dose of digoxin absolute bioavailability or lanoxicaps digoxin solution in capsules relative bioavailability. Pharmacokinetic evaluation of the digoxinamiodarone. Certaras phoenix platform is the leading pkpd modeling and simulation software used worldwide by 6,000 researchers at biopharmaceutical companies. Our software, pharmacokinetic modeling program pkmp will support data analysis for pharmacokinetic, clinical pharmacology, biopharmaceutics, and dissolution needs of new drug and generic product developments. High concentrations are found in the heart and kidneys, but the. It is effective for heart failure by helping the heart to beat.
Absorption of digoxin from lanoxin tablets has been 48 demonstrated to be 60% to 80% complete compared to an identical intravenous dose of digoxin 49 absolute bioavailability. Looking for pharmacokinetics software researchgate. Population pharmacokineticpharmacodynamic pkpd modeling of. The effect of steadystate ropinirole on plasma concentrations of. The disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Basic concepts in population modeling, simulation, and modela. Accp journals american college of clinical pharmacology. May 27, 2019 the doses of digoxin tablets used in controlled trials in patients with heart failure have ranged from 125 to 500 mcg 0. Impaired kidney function is the most important condition with an influence on the pharmacokinetics of digoxin. Digoxin has a distinct distribution phase, which lasts 68 hours and thus its disposition is best described by a twocompartment pharmacokinetic model. The effect of apixaban on the pharmacokinetics of digoxin.
Vd decrease 45lkg use vd equation when a patient is taking quinidine, what is affected regarding digoxin pharmacokinetics. Pharmacokinetics, bioavailability and serum levels of cardiac. In these studies, the digoxin dose has been generally titrated according to the patients age, lean body weight, and renal function. The software used to analyze digoxin pharmacokinetics was later extended to. Pharmacokinetics from ancient greek pharmakon drug and kinetikos moving, putting in motion. He recently has not seemed himself according to the nursing staff and a digoxin level is drawn. When lanoxin tablets are taken after meals, the rate of absorption 50 is slowed, but the total amount of digoxin absorbed is usually unchanged. Results macrogol 4000 coadministration was associated with a 30% decrease of digoxin auc and a 40% decrease in its c max p digoxin t max and t 12,z were not significantly altered. Digoxin incompletely distributes across the placental barrier. The positive inotropic effect of digoxin is caused by binding to sodium and potassiumactivated adenosine triphosphatase, also known as na,katpase or the sodium pump. Pharmacokinetic parameters were calculated using standard noncompartmental methods with the software phoenix winnonlin professional.
Massachusetts digoxin, the cardiac glycoside most frequently used in clinical practice in the united states, can be given orally or intravenously and has an excretory halflife of 36 to 48 hours in patients with serum creatinine and blood urea nitrogen values in the normal range. In chronic renal, what is affected regarding digoxin pharmacokinetics. Hanson, rn tucson, arizona amiodarone is known to raise serum digoxin levels. Methods as stated previously an advanced mathematical modeling method based on the theory of dynamic systems was employed to develop mathematical models of the pharmacokinetic behavior of digoxin in the volunteers investigated in the previous study by kramer et al. Digoxin and digitoxin convert atrial fibrillation and flutter to regular sinus rhythm with pharmacokinetically optimized dosage regimens. By its positive inotropic effect, digoxin increases the cardiac muscular force of contraction. Pharmacokinetics about 70 to 80% of an oral dose of digoxin is absorbed, mainly in the proximal part of the small intestine. The aims of this study were to collate literature data on the pharmacokinetics of biliary. It is a medication that is used for mild to moderate heart failure. Prednisolone is a wellknown corticosteroid used extensively for its antiinflammatory and immunosuppressive properties.
Applications of software packages in pharmacokinetics. Digitoxin appears to be rapidly and completely absorbed after oral or intramuscular administration although there have been no estimates of absolute bioavailabilily. Pharmacokinetics of diltiazem hydrochloride delayonset sustainedrelease pellet capsules in healthy volunteers 31 during the study. Pharmacokinetics of diltiazem hydrochloride delayonset. It was reported the pharmacokinetics pks of digoxin was not altered with rosuvastatin. Technical report 2012 2 laboratory of applied pharmacokinetics. It also relates to these processes to the intensity and time course of therapeutic and adverse effects of drugs and chemicals. Pharmacokinetics of digoxin, heart rate and pr ecg interval at rest were assessed. Previous population pharmacokinetics studies in pediatric patients non chinese demonstrated that the clearance of digoxin was influenced by the following demographic variables. Evaluate the pharmacokinetics of digoxin when coadministered. Aw, a 85 yo m takes digoxin for a history of atrial fibrillation. Digoxin is incompletely absorbed oral dose and has a substantial fraction cleared by kidneys with 7085% excreted in urine unchanged 22, 23, 25.
The fda recommends dextromethorphan as an in vitro and clinical substrate of cyp2d6. When lanoxin tablets are taken after meals, the rate of absorption. Pharmacokinetic and pharmacodynamic drug interactions. The effectiveness of digoxin in treating heart failure. Digoxin is extensively distributed in the tissues, as reflected by the large volume of distribution. Learn vocabulary, terms, and more with flashcards, games, and other study tools. Which pk pharmacokinetic software is most widely used by. Serum samples should be drawn just prior to the daily dose and no sooner than six hours after administration of the drug. Pharmacokinetic considerations for digoxin in older people.
The mechanism of action of digoxin involves stabilizing the sodium and potassium ion as they cross the plasma membrane in opposite directions using the nakatpase. The final model selected for the population prediction of digoxin clearance. When it comes to population pk modeling the question is. Digoxin metabolism in the elderly circulation 1969.
Phoenix uses graphical workflows to guide users in visualizing data flow and analysis pathways. About 70 to 80% of an oral dose of digoxin is absorbed, mainly in the proximal part of the small intestine. Jun 15, 2011 reported digoxin clearance of 53 mlmin1. Clinical pharmacokineticsdigoxin at the end of the. The effect of apixaban on the pharmacokinetics of digoxin and atenolol in healthy subjects charles frost,1 yan song,1 zhigang yu,2 jessie wang,3 lois s lee,4 alan schuster,5 allyson pollack,1 frank lacreta1 1exploratory clinical and translational research, bristolmyers squibb, princeton, nj, usa. The use of pharmacokinetics to adjust the dosing regimen can reduce the incidence of digoxin toxicity. The objective of this study is to apply machine learning techniques to predict the appropriateness of initial digoxin dosage. About digoxin it is a purified cardiac glycoside extracted from the foxglove plant, digitalis lanata. This openlabel study investigated the effect of exenatide coadministration on the steadystate plasma pharmacokinetics of digoxin. Dronedarone is safer than amiodarone as an antiarrhythmic, but concomitant administration with digoxin results in up to 2. Population pharmacokinetics of digoxin in pediatric patients. Digoxin data were analyzed by mixedeffects modeling according to a onecompartment steadystate pharmacokinetic model using nonmem software.
Three subjects were first given a digoxin tablet in the fasting state and subsequently received the same formulation in the fed state, to simulate a spurious oral bioavailability difference. As expected, when measured by peak serum digoxin concentration as well as by area under the serum digoxin concentrationtime curve the bioavailability of digoxin appeared to be higher in the fasting state. Figure 2 best fit for a simple population pharmacokinetics model. Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. The aims of this study were to collate literature data on the pharmacokinetics of biliary excretion of drugs used in pediatrics and to apply a physiologicallybased pharmacokinetic pbpk model to predict. Trough levels preferred or minimum 6 hours post dose due to long distribution t12 steady state. Clinical pharmacokinetics of digoxin linkedin slideshare. This was an openlabel, sequential, singlecenter study that evaluated the pharmacokinetics of digoxin when coadministered with pex168 in healthy adult subjects. The table is laid out in a common format for population modeling software. Tubular secretion is mediated by the multidrug active transporter, pglycoprotein. Digoxin is a cardiac glycoside, derived from tropical plants digitalis lanata and d purpurea 2.
Dec, 2012 the pharmacodynamic effects of digoxin, including toxic symptoms, are correlated with the uptake of digoxin in the heart after a single dose and with the steady state serum digoxin concentration during maintenance therapy. Feb 22, 2019 the tendency to impaired renal function and low lean body mass in the elderly influences the pharmacokinetics of digoxin, such that high serum digoxin levels and associated toxicity can occur quite readily, unless dosages of digoxin lower than those in nonelderly patients are used. Although some of the concepts associated with pharmacokinetics are much older eg, michaelismenten equation in 19, hill equation in 1908, the study of pharmacokinetics and pharmacodynamics pd has only been popularized over the last 60 years. Digoxin is the primary cardiac glycoside in clinical use. Digoxin generally does not have a role in the treatment of diastolic heart failure and is not a firstline therapy for managing atrial fibrillation in patients with heart failure. Digoxin tablets bp 250 micrograms summary of product. Which pk pharmacokinetic software is most widely used by the pharma industry.
Read 36 answers by scientists with 20 recommendations from their colleagues to the question asked by roland j. Digoxin is a highalert medication because of its narrow therapeutic range and high drugtodrug interactions ddis. Approximately 50% of digoxin toxicity cases are preventable, which motivated us to improve the treatment outcomes of digoxin. Digoxin and digitoxin convert atrial fibrillation and. Digoxin is a medication with the name brand of lanoxin. Pharmacokinetics is the study of the time course of drug absorption, distribution, metabolism, and excretion from the body. Characterising and avoiding the problem drugs aging 1991.
The industry standard for nca and pkpd modeling and. Jeo is a 71 yearold male with a past medical history of type 2 diabetes mellitus and hypertension, who is admitted for paroxysmal atrial fibrillation. Jun 15, 2015 this was an openlabel, sequential, singlecenter study that evaluated the pharmacokinetics of digoxin when coadministered with pex168 in healthy adult subjects. Population pharmacokinetics of digoxin in pediatric. Digoxin has a large volume of distribution, due to its high affinity for skeletal and cardiac muscles, intestines and kidney. The term pharmacokinetics pk is relatively young and was first introduced in 1953 wagner 1981. All patients had heart failure and were maintained on digoxin given orally. Hepatic metabolism of digoxin is known to play a minor role. Martinsuarez a, falcao ac, outeda m, hernandez fj, gonzalez mc, quero m, et al. Pharmacokinetics, bioavailability and serum levels of. Pharmacokinetic evaluation of the digoxin amiodarone interaction paul e. Population pharmacokinetics of digoxin in egyptian. There is only one study that has examined the relative bioavailability of two commercial digitoxin tablets usa and no differences. Specific objects are used for each action, such as data processing, table creation, creating figures and plots, performing modeling and simulation, and reporting results.
Pharmacokinetics describes how the body affects a specific xenobioticchemical after administration through the mechanisms of absorption and distribution, as well as the metabolic changes of the substance in the body e. The most comprehensive and widelyused software for pharmacokinetic pk, pharmacodynamic pd, and toxicokinetic tk modeling and simulation. In the foodeffect study, the high fat food diet used was. The bioavailability of digoxin varies from 50% to more than 90% of the oral dose 4, 23, 25 although this increases for gelatin capsules to nearly 100% intravenous is assumed to be 100% 4, 25. In a comparison of the pharmacokinetics of digoxin in young 3461 years and older 7291 years people, cusack et al. Digoxin tablets fda prescribing information, side effects. Nonlinear mixed effect modeling software version 5. These analyses are critical in drug development for cost and time savings. Digoxin is used in several cardiac pathologies such as atrial fibrillation and heart failure. In addition to the renal clearance of creatinine, the biovailability of the digoxin formulation used, the volume of distribution, the amount of extrarenal clearance, body weight and serum albumin concentration, are other factors which may modify the serum level of digoxin. The role of digoxin in the treatment of each of these disease states has. A simplified pbpk modeling approach for prediction of.
Introduction incorrect dosage of digoxin occurs frequently and is due in most cases to relative over or under dosage 9. Please let me know about your favorite pharmacokinetic software. Dec, 2012 the disposition kinetics of digitoxin have not been as thoroughly examined as those of digoxin. Most of the digoxin is eliminated unchanged by the kidneys. Pharmacokinetics, bioavailability and serum levels of cardiac glycosides thomas w. Pharmacokinetics sometimes abbreviated as pk, is a branch of pharmacology dedicated to. As expected, when measured by peak serum digoxin concentration.
Differential pharmacokinetics of digoxin in elderly patients drugs aging 2000. During process of the single and multiple dose clinical studies, all subjects were fed with the unified light foods diet and confined in special wards. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin it is widely used in the treatment of various heart conditions namely atrial fibrillation, atrial flutter and sometimes heart failure th. No effect of digoxin on rosuvastatin pharmacokinetics in.
The total duration of each subjects participation in the study was approximately 12 weeks, which included up to a 14day screening period, a 44day treatment period, and an. Pharmacokinetic evaluation of a drug transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin. Clinical pharmacokinetics of digitoxin springerlink. Taken together, pharmacokinetics, quantitative immunohistochemistry, and western blots strongly suggest that intestinal pgp plays a key role in systemic availability of digoxin, as was demonstrated for the interpatient variation in the oral bioavailability of cyclosporin. Effect of exenatide on the steadystate pharmacokinetics.
Heart rate and pr interval did not differ during the two therapeutic. Discuss how renal dysfunction affects loading and maintenance doses of digoxin. Nov 25, 20 understanding steady state pharmacokinetics posted on november 25, 20 august 9, 2017 by nathan teuscher steady state is an important term in pharmacokinetics, but it can often seem a bit abstract and confusing to many. In contrast, for intravenous administration, the plasma and urine halflives were very similar figure 3. At the same time, digoxin has a negative chronotropic effect that decreases heart rate by its influence on the cardiac electrical conduction pathway. Jul 01, 2014 understanding the clinical pharmacokinetics of digoxin will help us to improve in the dosage regimens design and therapeutics drugs monitoring.
Table1 label recoveries %administered dose after oral and intravenousadministration of 12oa h digoxin. A computerbased pharmacokinetic implementation for. Clinical pharmacokinetics digoxin jean nappi, pharm. Pharmacokinetic evaluation of a drug transporter cocktail. Based on this level, what is aws actual digoxin clearance. Digoxin is used for the treatment of congestive heart failure chf because of its inotropic effects on the myocardium and for the treatment of atrial fibrillation because of its chronotropic effects on the electrophysiological system of the heart.