Steady-state Pharmacokinetics Of Digoxin Research Articles

Effect of multiple doses of fimasartan, an angiotensin II receptor antagonist, on the steady-state pharmacokinetics of digoxin in healthy volunteers

Fimasartan (BR-A-657) is an angiotensin II receptor antagonist, recently approved as an antihypertensive agent. This study aimed to investigate whether administration of fimasartan has an effect on the steady-state pharmacokinetics of digoxin. An open-label, two-period, two-treatment, single-sequence, crossover study was conducted in 14 healthy male volunteers. On the first day of each 7-day treatment period, subjects received a loading dose of digoxin 0.5 mg, either alone or together with fimasartan 240 mg in the morning, followed by an additional dose of digoxin 0.25 mg after 6 h. On the subsequent 6 days, digoxin 0.25 mg, either alone or with fimasartan 240 mg was administered once daily. Serial blood samples for pharmacokinetics were collected up to 24 h after the last administration in each period. The geometric mean ratio and 90% confidence intervals (CI) for the Cmax,ss and AUCτ,ss of digoxin (with/without fimasartan) were 1.307 (1.123 - 1.520) and 1.087 (1.015 - 1.165), respectively. Study medications were well-tolerated without serious adverse events or clinically meaningful changes. Coadministration of fimasartan with digoxin does not result in clinically significant changes of digoxin pharmacokinetics at steady-state in healthy subjects.

Absence of an effect of a single-dose deferasirox on the steady-state pharmacokinetics of digoxin

Deferasirox (Exjade, ICL670) is a potent iron chelator, recently approved as first-line therapy for the treatment of blood-transfusion-related iron overload. Iron deposition in the heart may lead to cardiac dysfunction in patients with iron overload. Thus, the combination of cardiac glycosides and deferasirox is likely to be used in clinical practice. This study was designed to investigate the effect of deferasirox on steady-state pharmacokinetics of digoxin. As digoxin is a P-glycoprotein substrate, the trial also explored the potential of deferasirox to alter the pharmacokinetics of compounds transported by P-glycoprotein in general. An open-label, randomized, 2-period, crossover study was carried out with 16 healthy volunteers. During both treatment periods, each subject received daily oral doses of digoxin for 8 days (0.5 mg on Day 1 and 0.25 mg/day on Days 2 - 8). In one of these treatment periods, single oral deferasirox 20 mg/kg was coadministered with digoxin on Day 8. Pharmacokinetic parameters assessed at the end of each treatment period were compared using the standard statistical analysis for bioequivalence assessment. Deferasirox did not alter the steady-state pharmacokinetics of digoxin. The geometric mean ratios and 90% confidence intervals for Cmax and AUCtau of digoxin (with/without deferasirox) were 0.93 (0.82 - 1.06) and 0.91 (0.83 - 1.00), respectively, and thus within the equivalence limits of 0.8 - 1.25. The amount of digoxin excreted intact in urine was similarly unaltered by coadministration of deferasirox. This study shows that single-dose deferasirox has no effect on steady-state pharmacokinetics of digoxin. Therefore, no dose adjustment of digoxin is necessary when deferasirox and digoxin are coadministered. The lack of interaction suggests that deferasirox is unlikely to interact with P-glycoprotein substrates.

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.

Multiple doses of the antimuscarinic agent solifenacin do not affect the pharmacodynamics or pharmacokinetics of warfarin or the steady‐state pharmacokinetics of digoxin in healthy subjects

Solifenacin succinate is used for the treatment of overactive bladder (OAB). The potential for pharmacokinetic and/or pharmacodynamic interactions between solifenacin and warfarin or digoxin was investigated. The solifenacin-warfarin study was a two-period crossover trial conducted in healthy males. Subjects received warfarin on the 10th day of 16 days of dosing with either solifenacin or placebo. The solifenacin-digoxin study was an one-sequence crossover trial conducted in healthy males and females. Following a phase-in period for digoxin, solifenacin was administered concomitantly with the drug on days 9-18. The AUC(PT; 0-168 h) following a single dose of warfarin was unchanged in the presence of solifenacin [point estimate = 1.005; 90% confidence interval (CI) 0.98, 1.02)]. The AUC(0-infinity) values for both warfarin enantiomers were also unchanged. A small increase in the C(max) of digoxin was observed during treatment with solifenacin, but for AUC(ss,tau) and C(max) the 90% CI fell within the prespecified interval of 0.80-1.25. Combined administration of solifenacin and warfarin or digoxin was well tolerated. Since the pharmacokinetics and pharmacodynamics of a single dose of warfarin and the steady-state pharmacokinetics of digoxin were not affected by coadministration of solifenacin in healthy subjects, the need for dosing adjustments for digoxin and/or warfarin does not seem warranted.

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.

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

Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene.

We investigated the effect of polymorphisms in the P-glycoprotein (P-gp) MDR1 gene on steady-state pharmacokinetics of digoxin in Caucasians. According to earlier data, homozygous TT of the exon 26 complementary deoxyribonucleic acid (cDNA) 3435C>T polymorphism was associated with low P-gp expression in the human intestine. Eight healthy male homozygous carriers of the wild-type exon-26 3435C>T (CC), 8 heterozygous subjects (CT), and 8 homozygous mutant (TT) subjects were selected. Seven further MDR1 polymorphisms were determined. Digoxin was administered orally twice daily on the first two study days; on days 3 to 5, 0.25 mg was given in the morning. On day 5, kinetic parameters were analyzed for genotype-phenotype and haplotype-phenotype relationships. The area under the plasma concentration-time curve from time zero to 4 hours [AUC(0-4)] (P =.042) and C(max) (P =.043) values of digoxin were higher in subjects with the 3435TT genotype than in those with the 3435CC. No influence of other single nucleotide polymorphisms (SNPs) on digoxin parameters was detected. Comparison of genotypes deduced from SNPs 2677G>T (exon 21) and 3435C>T revealed significant differences for AUC(0-4) (P =.034) and C(max) (P =.039), which were substantiated by haplotype analysis. Haplotype 12 (2677G/3435T), which had a frequency of 13.3% in a randomly drawn Caucasian sample (n = 687), was associated (Mann-Whitney test) with higher AUC(0-4) values (P =.009) than were found in noncarriers (mean +/- SD, 5.7 +/- 0.9 microg. h/L [n = 7] versus 4.8 +/- 0.9 microg. h/L [n = 17]). Haplotype 11 (2677G/3435C) had lower AUC(0-4) values (P =.013) compared with those of noncarriers (mean +/- SD, 4.7 +/- 0.9 microg. h/L [n = 16] versus 5.6 +/- 0.9 microg. h/L [n = 8]). Results of haplotype analysis match data of other MDR1 studies. Haplotype 12 codes for high values of AUC(0-4) and C(max) of orally administered digoxin. Analysis of MDR1 haplotypes is superior to unphased SNP analysis to predict MDR1 phenotype.

Effect of dofetilide on the pharmacokinetics of digoxin

The effect of dofetilide on the steady-state pharmacokinetics of digoxin was evaluated in a randomized, double-blind study. Five days of dofetilide treatment did not significantly affect steady-state pharmacokinetic variables of digoxin compared with placebo; therefore, the use of dofetilide does not necessitate an adjustment in digoxin dose to maintain therapeutic digoxin levels.

The Effect of Telmisartan on the Steady‐State Pharmacokinetics of Digoxin in Healthy Male Volunteers

A multiple-dose, open-label, two-period, crossover randomized study was conducted in 12 healthy male volunteers to investigate the effect of multiple-dose telmisartan on the steady-state pharmacokinetics of digoxin. On day 1 of a 7-day medication period, subjects received a loading dose of digoxin 0.5 mg in the morning, followed by an evening dose of digoxin 0.25 mg, either alone or together with telmisartan 120 mg administered in the morning. On the subsequent 6 days, either digoxin 0.25 mg or digoxin 0.25 mg together with telmisartan 120 mg was administered once daily in the morning. Each 7-day medication period was separated by a washout period of > or = 14 days. A steady-state plasma concentration-time profile was assessed for digoxin during each period and for telmisartan during the period with the combined treatment. Multiple-dose telmisartan administered with digoxin resulted in higher serum digoxin concentrations than those observed after digoxin given alone. Geometric mean AUC144-168, Cmax, and Cmin values for digoxin when given in combination with telmisartan were higher by 22%, 50%, and 13%, respectively, compared with values when given alone. However, the 90% confidence interval for the geometric mean of Cmin was within the predefined 80% to 125% range of no interaction. During combination medication, digoxin tmax was shorter and Cmax/AUC144-168 increased, suggesting that the rise in digoxin Cmax may be due to more rapid drug absorption. Study medications were well tolerated, with the incidence, nature, and intensity of adverse events being similar during both medication periods. Also, no changes in vital signs or clinical laboratory tests were observed during the study. Although there was some evidence for a pharmacokinetic interaction between digoxin and telmisartan found in this study, the safety and tolerability of digoxin were unaffected by concurrent administration of telmisartan in the study population. Since any symptoms of overdose are related only to steady state and not peak concentrations and due to the fact that there was a lack of effect on serum trough levels of digoxin in this study, it is unlikely that the findings have any clinical relevance. The magnitude of increase in digoxin concentrations is comparable with increases observed with administration of calcium antagonists, carvedilol, ACE inhibitors such as captopril, and antiarrhythmic drugs such as amiodarone, quinidine, and propafenone. Monitoring of serum digoxin concentrations should be considered when patients first receive telmisartan and in the event of any changes in telmisartan dose.

Rosiglitazone Does Not Affect the Steady‐State Pharmacokinetics of Digoxin

Rosiglitazone is a potent insulin-sensitizing oral hypoglycemic agent of the thiazolidinedione class that works through activation of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) nuclear receptor and improves glycemic control in patients with non-insulin-dependent diabetes mellitus. The potential for a drug-drug interaction with oral digoxin was investigated. Subjects received both of the study regimens in a random sequence: digoxin 0.375 mg plus matching placebo for rosiglitazone orally each morning for 14 days or digoxin 0.375 mg plus 8 mg rosiglitazone orally each morning for 14 days. There was a 14-day washout period between sessions. Blood and urine were collected over 24 hours beginning on the morning of day 14 for measurement of digoxin concentrations. An equivalence statistical approach was used, with rosiglitazone considered to have no effect on the pharmacokinetics of digoxin if the 90% confidence interval (CI) for the ratio of digoxin plus rosiglitazone relative to digoxin plus placebo was completely contained within the range (0.80, 1.25) for the primary end points, AUC(0-24), and C24. Digoxin AUC(0-24) and C24 values were similar for digoxin 0.375 mg plus matching placebo (18.5 ng.h/mL and 0.579 ng/mL, respectively) and digoxin 0.375 mg plus rosiglitazone (19.1 ng.h/mL and 0.594 ng/mL, respectively). Point estimates were 1.05 (90% CI: 1.01, 1.10) for AUC(0-24) and 1.04 (90% CI: 0.98, 1.11) for C24. Oral and renal clearance were also similar between regimens. Digoxin alone or in combination with rosiglitazone was safe and well tolerated. The most common adverse experience was headache. Coadministration of digoxin with rosiglitazone had no significant effect on the safety or steady-state pharmacokinetics of digoxin.

Effect of Troglitazone on Urinary Excretion of 6β‐Hydroxycortisol

Coadministration of troglitazone reduces the plasma concentrations of terfenadine and ethinyl estradiol, Because these drugs are metabolized at least in part by cytochrome P450 3A (CYP3A), it is possible that troglitazone induces CYP3A activity, thereby reducing plasma concentrations of these agents. Known inducers of CYP3A, such as rifampin, phenytoin, carbamazepine, and phenobarbital, increase the urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to cortisol. This evaluation examined the effect of troglitazone on urinary excretion of 6β‐hydroxycortisol and the ratio of 6β‐hydroxycortisol to cortisol as a marker for CYP3A induction. Urine samples were collected from 11 subjects who completed a study evaluating the effect of multiple‐dose administration of troglitazone 400 mg once daily (days 11‐20) on the steadystate pharmacokinetics of digoxin (0.25 mg daily on days 1‐20). A single urine sample was collected at baseline on day 1, and 24‐hour urine samples were collected on days 10 and 20. Mean ± standard deviation 24‐hour excretion rate of cortisol was unchanged, whereas that of 6β‐hydroxycortisol increased during troglitazone administration. The ratio of 24‐hour urinary 6β‐hydroxy‐cortisol to cortisol excretion increased from 7.4 ± 2.7 on day 10 to 16.1 ± 6.2 on day 20. The ratio observed on day 10 was similar to that obtained at baseline. These results are consistent with the hypothesis that troglitazone induces CYP3A activity.

Concomitant troglitazone does not change the steady-state pharmacokinetics of digoxin,

Concomitant troglitazone does not change the steady-state pharmacokinetics of digoxin,

Effect of troglitazone on steady-state pharmacokinetics of digoxin.

Twelve healthy subjects participated in a study to determine the effect of multiple doses of troglitazone on the steady-state pharmacokinetics of digoxin. Subjects received digoxin 0.25 mg orally once daily on days 1 through 20 and 400 mg of troglitazone orally once daily on days 11 through 20. Serial plasma samples and 24-hour urine samples collected before and after the doses on days 10 and 20 were analyzed for digoxin using a radioimmunoassay method. Eleven subjects completed the study. Administration of multiple oral doses of digoxin and troglitazone was well tolerated. Mean values for maximum concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve from 0 to 24 hours (AUC0-24) of digoxin on day 10 were similar to those on day 20. Mean day 10 digoxin values for minimum concentration (Cmin), apparent oral clearance (Cl/F), total urinary excretion from 0 to 24 hours (Ae0-24), and renal clearance (Clr) were also similar to corresponding values on day 20. Thus, concomitant administration of multiple-dose troglitazone does not alter the steady-state pharmacokinetics of digoxin.

Pharmacokinetic effects of fluvastatin in patients chronically receiving digoxin

A double-blind, randomized, crossover study assessed the effects of a single 40-mg dose of fluvastatin on the steady-state pharmacokinetics of digoxin in chronically treated patients. After demonstrating consistent digoxin serum concentrations as part of the inclusion criteria, 18 patients received a single dose of either fluvastatin or placebo, with a 1-week washout period between crossover to the other treatment. For each patient, 14 serum samples were drawn and urine collected over 24 hours; all samples were assayed for digoxin using a fluorescence polarization immunoassay. The following pharmacokinetic parameters were determined using noncompartmental techniques: area under the curve for 24 hours (AUC 24); time to maximum concentration after digoxin (t max); maximum concentration after digoxin dosing (C max); concentration at 24 hours after fluvastatin or placebo (C min); total amount excreted in the urine over 24 hours (U 24); and urinary clearance (Cl ren). The pharmacokinetic data were analyzed for sequence, patient nested with sequence, and period and treatment differences using ANOVA, Schuirmann's two one-sided testing approach, confidence intervals, and power analysis. The AUC 24, C max, and t max for digoxin were considered bioequivalent with the two treatments. The differences in C max, U 24, and Cl ren were statistically significant but were not considered to be clinically relevant due to the low magnitude of the difference (<20%). There were no clinically significant adverse reactions attributable to either digoxin or fluvastatin.

The Effect of Captopril on Pharmacokinetics of Digoxin in Patients with Mild Congestive Heart Failure

The effect of captopril on steady-state pharmacokinetics of digoxin was studied in 12 patients with mild congestive heart failure (CHF; New York Heart Association functional class 1 or 2). Serum and urine digoxin concentrations were determined before and after a repeated administration of captopril in the patients on chronic digoxin therapy. The patients were taking digoxin, 0.25-0.375 mg/day, once daily, and were concurrently administered captopril, 37.5 mg/day, three times daily, for seven days. Peak serum concentration of digoxin (SCD) before and after captopril was 2.1 +/- 0.2, mean +/- SEM, and 2.0 +/- 0.1 ng/ml; the time to peak was 1.1 +/- 0.2 and 1.8 +/- 0.3 h; the terminal half-life (t1/2 alpha) was 10.9 +/- 1.0 and 8.7 +/- 0.9 h, and the area under the concentration-time curve to 24 h was 26.9 +/- 2.4 and 27.6 +/- 2.0 ng.h/ml. There was no significant difference between patients without and with captopril in SCD and its pharmacokinetic parameters. Renal digoxin clearance and creatinine clearance also showed no significant difference. After an administration of captopril, angiotensin-converting-enzyme (ACE) activity was well suppressed. These results suggest that captopril does not increase SCD in patients with CHF, and effectively suppresses ACE activity. Thus, modification in the dosage regimen of digoxin may be unnecessary in the case of coadministration with captopril.