Plasma Digoxin Research Articles

Measuring the Unbound Concentration Fails to Resolve Analytic Interferences in Digoxin Immunoassays

Therapeutic drug monitoring of digoxin is well established in the clinical management of cardiac patients treated with the drug. Recently, target concentrations have been revised in patients with congestive heart failure to 0.5 to 0.8 microg/L, challenging the sensitivity limits of most immunoassays. These widely used methods are often criticized, particularly on specificity grounds resulting from interference from exogenous and endogenous sources. One solution to remove higher molecular weight interference has been to ultrafilter plasma samples before assaying. The present study included 261 patient digoxin samples and compared two commercial ultrafiltration devices (Centrifree and Micrcon) that share the same separation membrane (YM-30). The results showed widely discordant apparent unbound digoxin concentrations in the ultrafiltrate from these devices with a Deming regression line of Centrifree = 1.31 x Micrcon + 0.042 (95% confidence interval for slope of 1.237 to 1.391) and apparent unbound fractions ranging from 15% to 610% of the unfiltered plasma digoxin concentrations, suggesting that ultrafiltration did not resolve such interference issues. The concept of measuring lower unbound digoxin concentrations as a result of lower therapeutic range for total (bound plus unbound) digoxin will also render most immunoassays insensitive and inappropriately calibrated. There is a strong imperative to review digoxin monitoring practices in the light of current clinical imperatives for both specificity and sensitivity reasons.

Gauging the clinical significance of P‐glycoprotein‐mediated herb‐drug interactions: Comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics

Concomitant administration of botanical supplements with drugs that are P-glycoprotein (P-gp) substrates may produce clinically significant herb-drug interactions. This study evaluated the effects of St. John's wort and Echinacea on the pharmacokinetics of digoxin, a recognized P-gp substrate. Eighteen healthy volunteers were randomly assigned to receive a standardized St. John's wort (300 mg three times daily) or Echinacea (267 mg three times daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (300 mg twice daily, 7 days) and clarithromycin (500 mg twice daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin 0.25 mg) was administered orally before and after each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), elimination half-life, and maximum serum concentration were used to assess the effects of St. John's wort, Echinacea, rifampin, and clarithromycin on digoxin disposition. St. John's wort and rifampin both produced significant reductions (p < 0.05) in AUC((0-3)), AUC((0-24)), and C(max), while clarithromycin increased these parameters significantly (p < 0.05). Echinacea supplementation did not affect digoxin pharmacokinetics. Clinically significant P-gp-mediated herb-drug interactions are more likely to occur with St. John's wort than with Echinacea.

Validation and application of a 96-well format solid-phase extraction and liquid chromatography–tandem mass spectrometry method for the quantitation of digoxin in human plasma

To evaluate the pharmacokinetics of digoxin in humans, a sensitive and specific LC/MS/MS method was developed and validated for the determination of digoxin concentrations in human plasma. The method was shown to be more sensitive, specific, accurate, and reproducible than common techniques such as RIA. For detection, a LC/MS/MS system with electro spray ionization tandem mass spectrometry in the positive ion-multiple reaction-monitoring (MRM) mode was used to monitor precursor to product ions of m/ z 798.5–51.5 for digoxin and m/ z 782.5–35.5 for the internal standard, digitoxin. The method was validated over a concentration range of 0.02–5 ng/mL and was found to have acceptable accuracy, precision, linearity, and selectivity. The mean extraction recovery from spiked plasma samples was above 80%. Imidafenacin, coadministered in a drug–drug interaction study, had no detectable influence on the determination of digoxin in human plasma. The novel method was applied to a drug–drug interaction study of digoxin and imidafenacin and the characterization of steady-state pharmacokinetics of digoxin in humans after oral administration at a dose of 0.25 mg on days 1 and 2 followed by 0.125 mg daily doses on days 3 through 8.

Sensitive and specific LC‐MS assay for quantification of digoxin in human plasma and urine

Digoxin, a commonly prescribed cardiac glycoside with a narrow therapeutic window, is routinely used in pharmacokinetic studies to assess the in vivo activity of the drug efflux pump P-glycoprotein. To minimize adverse events, a sub-therapeutic dose of digoxin is usually administered, producing low plasma concentrations requiring a sensitive detection technique. Commonly available immunoassay techniques do not provide the required sensitivity to measure these low plasma concentrations and are potentially non-specific in certain subject populations. Previously published mass spectrometric techniques require either large plasma volumes or a tandem mass spectrometer. To overcome these challenges we have developed a sensitive and specific LC-MS method for the quantification of digoxin in small volumes of human plasma and urine. Plasma (1 mL) was extracted with methyl t-butyl ether under basic conditions followed by LC-MS detection of the sodium adducts of digoxin (803.4 m/z) and digitoxin (787.4 m/z, internal standard). Linearity and accuracy were demonstrated across a wide range of digoxin plasma concentration (0.05-1.5 ng/mL). This specific, sensitive, validated digoxin LC-MS assay can be used to quantify sub-therapeutic digoxin plasma concentrations in men and women (pregnant and non-pregnant).

No Effect of Imidafenacin, a Novel Antimuscarinic Drug, on Digoxin Pharmacokinetics in Healthy Subjects

Plasma digoxin concentrations are increased by the coadministration of anticholinergic drugs, such as propantheline, which decrease gastrointestinal motility. The present study evaluated the effect of imidafenacin, a novel anticholinergic drug, on the pharmacokinetics of digoxin. The effect of imidafenacin on the pharmacokinetics of digoxin was examined in 14 healthy Japanese male subjects in a single-centre, open-label, randomized, two-way crossover study. Subjects received a daily oral dose of digoxin 0.25 mg on days 1 and 2 and digoxin 0.125 mg on days 3 to 8 (period 1). Following a 2-week washout period, digoxin was administered orally for 8 days in a similar manner (period 2). A twice daily dose of imidafenacin 0.1 mg was concomitantly administered with digoxin for 8 days either in period 1 or 2. The geometric mean ratios [GMR] (90% confidence intervals [CIs]) for digoxin C(max) and AUC(0-24) (with/without imidafenacin) at steady state were 0.88 (0.74, 1.04) and 1.00 (0.90, 1.10), respectively. The 90% CIs of GMR for digoxin trough concentration, urinary excretion amount and renal clearance at steady state fell within the range of 0.8 to 1.25. The steady-state pharmacokinetics of digoxin is not affected by concomitant administration of imidafenacin in healthy subjects.

Absence of an Interaction Between Tigecycline and Digoxin in Healthy Men

To evaluate a potential interaction between tigecycline and digoxin using pharmacokinetic and pharmacodynamic assessments. Open-label, three-period, one-sequence crossover study. Hospital-affiliated, inpatient clinical pharmacology unit. Twenty healthy men. Tigecycline 100 mg was administered intravenously as a single dose on day 1 (period 1). Digoxin was administered as a 0.5-mg oral loading dose on day 7, followed by 0.25 mg/day on days 8-14 (period 2). Digoxin 0.25 mg/day was continued on days 15-19; in addition, on day 15, a loading dose of tigecycline 100 mg was administered intravenously, followed by 50 mg every 12 hours starting on the evening of day 15 through the morning of day 19 (period 3). Pharmacokinetic assessments were performed on days 1 and 19 for tigecycline and on days 14 and 19 for digoxin. Electrocardiographic parameters were measured at baseline and on days 1, 14, and 19 to assess digoxin pharmacodynamics. Serum tigecycline concentrations were determined by liquid chromatography with tandem mass spectrometry detection, and plasma and urine digoxin concentrations were determined by radioimmunoassay. Tigecycline area under the concentration-time curve (AUC), AUC from 0-12 hours (AUC(0-12)), weight-normalized clearance, and mean resistance time were not affected by concomitant multiple-dose digoxin administration, but tigecycline half-life was decreased during period 1, apparently due to fewer detectable terminal concentrations in some subjects. Digoxin steady-state AUC(0-24), weight-normalized oral dose clearance, cumulative amount of drug excreted in urine over 24 hours, renal clearance, and QTc (change from baseline) were not affected by multiple-dose tigecycline administration. No significant effects of tigecycline on digoxin pharmacokinetics and pharmacodynamics were noted, but a small effect of digoxin on tigecycline pharmacokinetics cannot be ruled out due to design issues with period 1 of the study.

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.

Endogenous and Exogenous Cardiac Glycosides and their Mechanisms of Action

Cardiac glycosides have been used for decades to treat congestive heart failure. The recent identification of cardiotonic steroids such as ouabain, digoxin, marinobufagenin, and telocinobufagin in blood plasma, adrenal glands, and hypothalamus of mammals led to exciting new perspectives in the pathology of heart failure and arterial hypertension. Biosynthesis of ouabain and digoxin occurs in adrenal glands and is under the control of angiotensin II, endothelin, and epinephrine released from cells of the midbrain upon stimulation of brain areas sensing cerebrospinal Na(+) concentration and, apparently, the body's K(+) content. Rapid changes of endogenous ouabain upon physical exercise may favor the economy of the heart by a rise of intracellular Ca(2)(+) levels in cardiac and atrial muscle cells. According to the sodium pump lag hypothesis, this may be accomplished by partial inhibition of the sodium pump and Ca(2+) influx via the Na(+)/Ca(2+) exchanger working in reverse mode or via activation of the Na(+)/K(+)-ATPase signalosome complex, generating intracellular calcium oscillations, reactive oxygen species, and gene activation via nuclear factor-kappaB or extracellular signal-regulated kinases 1 and 2. Elevated concentrations of endogenous ouabain and marinobufagenin in the subnanomolar concentration range were found to stimulate proliferation and differentiation of cardiac and smooth muscle cells. They may have a primary role in the development of cardiac dysfunction and failure because (i) offspring of hypertensive patients evidently inherit elevated plasma concentrations of endogenous ouabain; (ii) such elevated concentrations correlate positively with cardiac dysfunction, hypertrophy, and arterial hypertension; (iii) about 40% of Europeans with uncomplicated essential hypertension show increased concentrations of endogenous ouabain associated with reduced heart rate and cardiac hypertrophy; (iv) in patients with advanced arterial hypertension, circulating levels of endogenous ouabain correlate with BP and total peripheral resistance; (v) among patients with idiopathic dilated cardiomyopathy, high circulating levels of endogenous ouabain and marinobufagenin identify those individuals who are predisposed to progressing more rapidly to heart failure, suggesting that endogenous ouabain (and marinobufagenin) may contribute to toxicity upon digoxin therapy. In contrast to endogenous ouabain, endogenous marinobufagenin may act as a natriuretic substance as well. It shows a higher affinity for the ouabain-insensitive alpha(1) isoform of Na(+)/K(+)-ATPase of rat kidney tubular cells and its levels are increased in volume expansion and pre-eclampsia. Digoxin, which is synthesized in adrenal glands, seems to counteract the hypertensinogenic action of ouabain in rats, as do antibodies against ouabain, for example, (Digibind) and rostafuroxin (PST 2238), a selective ouabain antagonist. It lowers BP in ouabain- and adducin-dependent hypertension in rats and is a promising new class of antihypertensive medication in humans.

Effect of Goldenseal (Hydrastis canadensis) and Kava Kava (Piper methysticum) Supplementation on Digoxin Pharmacokinetics in Humans

Phytochemical-mediated modulation of P-glycoprotein (P-gp) and other drug transporters may give rise to many herb-drug interactions. Serial plasma concentration-time profiles of the P-gp substrate, digoxin, were used to determine whether supplementation with goldenseal or kava kava modified P-gp activity in vivo. Twenty healthy volunteers were randomly assigned to receive a standardized goldenseal (3210 mg daily) or kava kava (1227 mg daily) supplement for 14 days, followed by a 30-day washout period. Subjects were also randomized to receive rifampin (600 mg daily, 7 days) and clarithromycin (1000 mg daily, 7 days) as positive controls for P-gp induction and inhibition, respectively. Digoxin (Lanoxin, 0.5 mg) was administered p.o. before and at the end of each supplementation and control period. Serial digoxin plasma concentrations were obtained over 24 h and analyzed by chemiluminescent immunoassay. Comparisons of area under the curve (AUC)((0-3)), AUC((0-24)), C(max,) CL/F, and elimination half-life were used to assess the effects of goldenseal, kava kava, rifampin, and clarithromycin on digoxin pharmacokinetics. Rifampin produced significant reductions (p < 0.01) in AUC((0-3)), AUC((0-24)), CL/F, t(1/2), and C(max), whereas clarithromycin increased these parameters significantly (p < 0.01). With the exception of goldenseal's effect on C(max) (14% increase), no statistically significant effects on digoxin pharmacokinetics were observed following supplementation with either goldenseal or kava kava. When compared with rifampin and clarithromycin, supplementation with these specific formulations of goldenseal or kava kava did not appear to affect digoxin pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo.

Rapid Quantitation of Digoxin in Human Plasma and Urine Using Isotope Dilution Liquid Chromatography‐Tandem Mass Spectrometry

A rapid LC/MS/MS assay to quantitate digoxin in human plasma and urine has been developed and validated using a Packard liquid handling systems‐Multiprobe® II AMP8E1. Following automatic solid phase extraction on Waters Oasis HLB 30 mg 96 plates, digoxin and its internal standard (Digoxin D3) were analyzed by reverse phase chromatography (LUNA C18, 5 µm, 150×2 mm), and introduced into the mass spectrometer (Sciex ‐ API 3000) via the turboIonspray ion source operating in positive mode. The assay was validated for human plasma and human urine over a concentration range of 0.2–20 ng/mL and 1–100 ng/mL, respectively, using 0.5 mL of sample. The between day and within day coefficients of variation for all matrices were <17% at the concentrations of lower limit of quantification (LLOQ), and <13% at other quality control concentrations. The average recovery was 80.3% from plasma and 74.3% from urine. No matrix effect was observed. Freeze‐thaw stability, stability of digoxin in matrix, and stability of extracted samples were also evaluated. The mean concentration after three freeze‐thaw cycles was within±3.2% of the nominal value in plasma and within±11.4% of the nominal value in urine. After storage for 4 hours at room temperature, greater than 97.2% of digoxin remained in plasma and 96% remained in urine. Digoxin in extract was stable in the autosampler at+5°C for 77 hours in plasma and 80 hours in urine.

Telithromycin-Induced Digoxin Toxicity and Electrocardiographic Changes

A 58-year-old woman who had been taking digoxin 0.25 mg/day for more than 35 years for heart palpitations after mitral valve repair was prescribed a 5-day course of telithromycin for acute bronchitis. On the sixth day of therapy, she came to the emergency department complaining of general malaise and having experienced three episodes of syncope over the previous 2 days. Laboratory analysis revealed elevated digoxin plasma levels, and electrocardiography showed several nonspecific repolarization anomalies. Telithromycin is known to increase digoxin plasma levels; however, the clinical significance of this interaction is not known. To our knowledge, this is the first report of elevated plasma digoxin levels associated with signs and symptoms of toxicity. This drug interaction-determined as probable according to the Naranjo adverse drug reaction probability scale-may be mediated by P-glycoprotein. By inhibiting the transport of digoxin by P-glycoprotein, telithromycin may have decreased digoxin elimination in the intestinal lumen and its renal tubular excretion, resulting in elevated plasma levels and drug toxicity. Clinicians should be aware of possible digoxin toxicity after concomitant administration with telithromycin, especially in patients who are at risk, such as those with electrolyte abnormalities and decreased renal function.

Therapeutic Drug Monitoring of Digoxin

Digoxin is a cardioactive drug with a narrow therapeutic range. Therapeutic drug monitoring is essential in clinical practice for efficacy as well as to avoid digoxin toxicity. Immunoassays are commonly used in clinical laboratories for determination of serum or plasma digoxin concentrations. Unfortunately, digoxin immunoassays are affected by both endogenous and exogenous compounds. Endogenous compounds are termed 'digoxin-like immunoreactive substances' (DLIS), which are found in elevated concentrations in volume-expanded patients. Exogenous compounds that interfere with digoxin assays are various drugs such as spironolactone, potassium canrenoate as well as Digibind (Fab fragment of antidigoxin antibody), which is used in treating life-threatening digoxin overdose. Moreover, various Chinese medicines such as Chan Su, Lu-Shen Wan and oleander-containing herbal preparations also interfere with serum digoxin measurements by immunoassays. Monitoring unbound (free) digoxin concentration may under certain circumstances eliminate such interferences. Clinicians should be aware of limitations of therapeutic drug monitoring of digoxin using immunoassays.

Effect of Lasofoxifene on the Pharmacokinetics of Digoxin in Healthy Postmenopausal Women

Lasofoxifene is in late-stage development for the prevention and treatment of osteoporosis. Digoxin is commonly prescribed for arrhythmias and congestive heart failure, has a narrow therapeutic index, and may be coadministered with lasofoxifene. This study was conducted to determine the effect of lasofoxifene (4-mg loading dose on day 11 followed by 0.5 mg/d on days 12-20) on the steady-state pharmacokinetics of digoxin (0.25 mg/d on days 1-20) in 12 healthy postmenopausal women. On days 10 and 20, blood and urine samples were collected for 24 hours to determine digoxin concentrations. The 90% confidence interval (CI) of least squares mean ratio for maximum concentration (C(max)) and area under the plasma concentration-time curve (AUC) was calculated. Lasofoxifene had no effect on digoxin plasma pharmacokinetics with a ratio (90% CI) of 95.4% (84.6%-107%) and 103% (97.7%-108%) for C(max) and AUC(0-24), respectively. The ratio of the percentage of dose eliminated unchanged in urine in 24 hours was 127% (116% to 142%). Coadministration of lasofoxifene had no effect on the steady state pharmacokinetics of digoxin.

The role of fluorescence polarization immuno-assay in the diagnosis of plant-induced cardiac glycoside poisoning livestock in South Africa

Poisoning with cardiac glycoside-containing plants is collectively the most important plant-associated poisoning of livestock in southern Africa. As a diagnosis of this significant poisoning is currently based on circumstantial evidence, a practical chemical procedure indicating the presence of cardiac glycosides in plants and animal specimens would be of considerable benefit. The fluorescence polarization immunoassay (FPIA) method, used to determine digoxin plasma levels in humans and dogs, was adapted to estimate cardiac glycoside levels in known cardiac-glycoside-containing plants as well as in the rumen and organs of dosed sheep. Positive FPIA values were obtained with bufadienolide-containing plants, while negative results were obtained with plants not known to contain cardiac glycosides. The FPIA has aided in the diagnosis of cardiac glycoside poisoning in livestock and game in 30 outbreaks examined at the Division of Toxicology, Onderstepoort Veterinary Institute. Each outbreak is briefly described. As a result of this assay, a better understanding of cardiac glycoside poisoning has been reached.

Effect of Exenatide on the Steady‐State Pharmacokinetics of Digoxin

This open-label study investigated the effect of exenatide coadministration on the steady-state plasma pharmacokinetics of digoxin. A total of 21 healthy male subjects received digoxin (day 1, 0.5 mg twice daily; days 2-12, 0.25 mg once daily) and exenatide (days 8-12, 10 microg twice daily). Digoxin plasma and urine concentrations were measured on days 7 and 12. Exenatide coadministration did not change the overall 24-hour steady-state digoxin exposure (AUCtau,ss) and Cmin,ss but caused a 17% decrease in mean plasma digoxin Cmax,ss (1.40 to 1.16 ng/mL) and an increase in digoxin tmax,ss (median increase, 2.5 hours). Although the decrease in digoxin Cmax,ss was statistically significant, peak concentrations were within the therapeutic concentration range in all subjects. Digoxin urinary pharmacokinetic parameters were not altered. Gastrointestinal symptoms, the most common adverse effects of exenatide, decreased over time. Exenatide administration does not cause any changes in digoxin steady-state pharmacokinetics that would be expected to have clinical sequelae; thus, dosage adjustment does not appear warranted, based on pharmacokinetic considerations.

Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein

Digoxin is a drug with a narrow therapeutic index, which is a substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to the inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidney. It is well known that serum concentrations of digoxin increase considerably in humans if propafenone is given simultaneously. However, it has not been investigated in detail whether propafenone and its metabolites are substrates and/or inhibitors of human P-glycoprotein. The aim of this study, therefore, was to investigate the P-glycoprotein-mediated transport and inhibition properties of propafenone and its major metabolites 5-hydroxypropafenone and N-desalkylpropafenone in Caco-2 cell monolayers. Inhibition of P-glycoprotein-mediated transport by propafenone and its metabolites was determined using digoxin as a P-glycoprotein substrate. No polarised transport was observed for propafenone and N-desalkylpropafenone in Caco-2 cell monolayers. However, 5-hydroxypropafenone translocation was significantly greater from basal-to-apical compared with apical-to-basal (P(app) basal-apical vs. P(app) apical-basal, 10.21+/-2.63 x 10(-6) vs. 4.34+/-1.84 x 10(-6) cm/s; P<0.01). Moreover, propafenone, 5-hydroxypropafenone and N-desalkylpropafenone inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 6.8, 19.9, and 21.3 microM, respectively. In summary, whereas propafenone and N-desalkylpropafenone are not substrates of P-glycoprotein, 5-hydroxypropafenone is translocated by human P-glycoprotein across cell monolayers. In addition, propafenone and its two major metabolites 5-hydroxypropafenone and N-desalkylpropafenone are inhibitors of human P-glycoprotein and therefore contribute to the digoxin-propafenone interaction observed in humans.

Evaluation of the effect of lasofoxifene (LASO) on the pharmacokinetics (PK) of digoxin

Background LASO, a next-generation selective estrogen receptor modulator, is in late stage development for the prevention and treatment of osteoporosis. LASO has a long half-life (6 days) and less than 2% of the dose is recovered unchanged in urine. Both oxidative and conjugative metabolism contribute to its elimination. Digoxin is commonly prescribed for arrhythmias and congestive heart failure, has a narrow therapeutic index and may be coadministered with LASO. Objectives To determine the effect of LASO on the steady-state PK of digoxin. Methods This was a 2-period, fixed-sequence study in 12 healthy postmenopausal women. During days 1–20, all subjects received digoxin (0.25 mg/day). On day 11, all subjects received 4 mg loading dose of LASO followed by 0.5 mg/day on days 12–20. On Days 10 and 20, blood and urine samples were collected for up to 24 hours for determination of digoxin concentrations. The 90% CI of least squares mean ratio for Cmax and AUC was calculated. Results LASO had no effect on digoxin plasma PK with ratio (90% CI) of 95.4% (84.6% to 107%) and 103% (97.7% to 108%) for Cmax and AUC0-24, respectively. Results were within the 80% to 125% acceptance range. However, the ratio of Ae% was 127% (116% to 142%). Conclusions Coadministration of LASO had no effect on the steady-state pharmacokinetics of digoxin. Clinical Pharmacology & Therapeutics (2005) 77, P45–P45; doi: 10.1016/j.clpt.2004.12.064

Assessment of milk thistle and black cohosh supplementation on digoxin pharmacokinetics

Background Phytochemical-mediated modulation of p-glycoprotein (P-gp) and other drug transporters may underlie many herb-drug interactions. Serial plasma concentration-time profiles of digoxin (DIG) (a P-gp substrate) were used to determine whether supplementation with milk thistle (MT) or black cohosh (BC) modulated P-gp activity in vivo. Methods Sixteen healthy volunteers were randomly assigned to receive each supplement, on separate occasions, for 14 days followed by a 30-day washout period. Subjects were also randomized to receive rifampin (RIF) (600 mg daily for 7 days) and clarithromycin (CLT) (1000 mg daily for 7 days) as positive controls for P-gp induction and inhibition, respectively. DIG (Lanoxicaps, 0.4 mg) was administered orally before and at the end of each supplementation and control period. Serial DIG plasma concentrations were obtained over 24 hours. Comparisons of AUC, Cmax, and Tmax were used to assess the effects of MT, BC, RIF, and CLT on DIG pharmacokinetics. Results RIF produced significant reductions (p<0.01) in AUC and Cmax, while CLT increased these parameters significantly (p<0.01). No statistically significant effects on DIG pharmacokinetics were observed following supplementation with either MT or BC, although BC approached significance for AUC (p= 0.05). Conclusions When compared to RIF and CLT, supplementation with MT or BC did not appear to affect DIG pharmacokinetics, suggesting that these supplements are not potent modulators of P-gp in vivo. Clinical Pharmacology & Therapeutics (2005) 77, P49–P49; doi: 10.1016/j.clpt.2004.12.078

Development of a model based on body composition to predict drug kinetics: II. Application of the model to the use of digoxin in elderlies

The applicability of a kinetic model for the prediction of steady-state blood levels, based on body composition as assessed by bioelectric impedance analysis (BIA), was applied to a population of elderly patients, candidates for digoxin therapy. Elderlies, all >70 years of age, underwent standard laboratory and clinical evaluation but no further characterization of liver or renal function. These 72 patients were given 0.125 mg digoxin for 5 days, in order to reach steady-state levels. Treatment was then interrupted and samples were collected 2 and 48 h after the last administration. Plasma digoxin levels were determined both by the immunochemical method with TDX and according to the BIA method described in the accompanying paper. Plasma levels calculated and measured in 2 h samples did not differ statistically, but levels were about 15% higher in the directly measured samples. There was a similar underestimation, i.e. about 15%, for the 48 h calculated levels. However, only approximately 5% of the levels were outside of the 95% confidence intervals as determined from the directly measured levels. These findings indicate that digoxin levels, calculated based on a BIA evaluation, may be sufficiently reliable, in the majority of patients, to allow direct determination of the more appropriate doses of digoxin.

Lack of clinically significant interaction between steady state tolvaptan and digoxin in healthy volunteers

Tolvaptan (TLV) is a selective vasopressin receptor (V2) antagonist being studied for several indications. Digoxin (DIG) is expected to be frequently co-administered with TLV. The objectives of this study were to determine the effect of TLV administration on steady state DIG pharmacokinetics (PK) and the effect of DIG on TLV PK. This study was an open-label, sequential design in 14 healthy men and women. Subjects received a single dose of 60 mg TLV on Day 1 followed by a 3-day washout. Following digoxin loading doses on Day 4, subjects received 0.25 mg DIG QD on Days 5 through 16. On Days 12 through 16, subjects also received 60 mg TLV QD. Plasma concentrations of TLV and metabolite were determined by HPLC-MS/MS. Serum and urine DIG were determined by turbidometric immunoassay. The table below summarizes the ratios of the Cmax and AUC0-24h geometric means and their 90% confidence intervals (90% CI) for steady state DIG+TLV vs. DIG alone and for a single oral dose of TLV with steady state DIG vs. TLV alone. Although plasma DIG concentrations were elevated, there were no clinically relevant changes in body weight, heart rate, systolic or diastolic blood pressure, ventricular rate or QTc (Bazett's) interval between Day 11 (DIG alone) and Day 16 (DIG + TLV). Therefore, there is no clinically significant interaction between DIG and TLV. Clinical Pharmacology & Therapeutics (2004) 75, P37–P37; doi: 10.1016/j.clpt.2003.11.139 Table 1. Analytes Parameter Cmax AUC0–24h Digoxin Day 16/Day 11 Ratio 1.27 1.18 90% CI 1.085–1.496 1.073–1.286 Tolvaptan Day 12/Day 1 Ratio 1.11 0.97 90% CI 0.885–1.395 0.758–1.251