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Patients with permanent atrial fibrillation and additional cardiac risk factors were randomly assigned to receive either dronedarone or placebo. At a median of 3.5 months, the risk of major adverse cardiovascular events was significantly increased with dronedarone. Dronedarone is a new antiarrhythmic agent that is used to restore sinus rhythm and to reduce rates of hospitalization for cardiovascular causes in patients with intermittent (paroxysmal or persistent) atrial fibrillation. 1 In ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter; ClinicalTrials.gov number, NCT00174785), 4628 patients with intermittent atrial fibrillation were randomly assigned to receive either dronedarone or placebo. Dronedarone reduced the incidence of the primary outcome of unplanned hospitalization for cardiovascular causes or death. Significant . . .

Background The presence and role of endogenous digoxin-like cardiotonic steroids (CTS) in humans is controversial. This study utilises a novel pipeline to quantify CTS and examines their interaction with digoxin within a randomised trial. Methods The RAte control Therapy Evaluation in permanent Atrial Fibrillation (RATE-AF) trial randomised patients with permanent AF and symptoms of heart failure to low-dose digoxin or beta-blocker therapy; clinicaltrials.gov NCT02391337. Circulating CTS were detected and quantified using a new ultra-high-performance liquid chromatography tandem mass spectrometry (LC–MS/MS) pipeline. Results All 160 participants of the RATE-AF trial were included, with mean age 76 years (SD 8) and 46% women. Endogenous CTS detected and quantified in baseline samples included digoxigenin and digitoxigenin, plus low or unquantifiable levels of ouabain, telocinobufagin, cinobufagin, marinobufagenin, bufalin, cinobufotalin, dihydroouabain, and ouabagenin. Compared to beta-blockers, patients randomised to digoxin had better functional outcomes at 12 months for heart failure (− 0.57 New York Heart Association class, 95% CI − 0.82 to − 0.32; p  < 0.001) and atrial fibrillation (odds ratio 2.24 for a two-class improvement in modified European Heart Rhythm Association class, 95% CI 1.43–3.84; p  < 0.001), with lower NT-pro-B-type natriuretic peptide (geometric mean ratio 0.78, 95% CI 0.61 to 0.99; p  = 0.006). No interactions were observed for any baseline CTS with each outcome. Digoxin was associated with fewer adverse events (odds ratio 0.16, 95% CI 0.07–0.34; p  < 0.001), again without any interaction from circulating CTS. Digoxin levels by LC–MS/MS were strongly correlated with measurement by a clinical immunoassay ( r  = 0.87; p  < 0.001), and treatment with digoxin did not affect CTS concentrations at 6-month follow-up. Conclusions A range of CTS are detected in the circulation of patients with atrial fibrillation and heart failure. Within this randomised trial but limited by low circulating levels, CTS do not appear to interact with the ability of digoxin to improve wellbeing compared to conventional first-line treatment with beta-blockers. Graphical Abstract

Background and Objective Vandetanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) signalling, indicated for the treatment of medullary thyroid cancer. We investigated potential drug–drug interactions between vandetanib and metformin [organic cation transporter 2 (OCT2) substrate; NCT01551615]; digoxin [P-glycoprotein (P-gp) substrate; NCT01561781]; midazolam [cytochrome P450 (CYP) 3A4 substrate; NCT01544140]; omeprazole (proton pump inhibitor) or ranitidine (histamine H 2 -receptor antagonist; both NCT01539655). Methods Four open-label, phase I studies were conducted in healthy volunteers: n  = 14 (metformin), n  = 14 (digoxin), n  = 17 (midazolam), n  = 16 (omeprazole), n  = 18 (ranitidine). Three of these comprised the following regimens: metformin 1000 mg ± vandetanib 800 mg, midazolam 7.5 mg ± vandetanib 800 mg, or digoxin 0.25 mg ± vandetanib 300 mg. The randomized study comprised vandetanib 300 mg alone and then either (i) omeprazole 40 mg (days 1–4), and omeprazole + vandetanib (day 5); or (ii) ranitidine 150 mg (day 1), and ranitidine + vandetanib (day 2). The primary objective assessed metformin, digoxin, midazolam and vandetanib pharmacokinetics. Results Vandetanib + metformin increased metformin area under the plasma concentration–time curve from zero to infinity (AUC 0–∞ ) and maximum observed plasma concentration (C max ) by 74 and 50 %, respectively, and decreased the geometric mean metformin renal clearance (CL R ) by 52 % versus metformin alone. Vandetanib + digoxin increased digoxin area under the concentration-time curve from zero to the last quantifiable concentration (AUC 0–last ) and C max by 23 and 29 %, respectively, versus digoxin alone, with only a 9 % decrease in CL R . Vandetanib had no effect on midazolam exposure. Vandetanib exposure was unchanged during co-administration with omeprazole/ranitidine. Treatment combinations were generally well tolerated. Conclusion Patients receiving vandetanib with metformin/digoxin may require additional monitoring of metformin/digoxin, with dose adjustments where necessary. Vandetanib with CYP3A4 substrates or omeprazole/ranitidine is unlikely to result in clinically relevant drug–drug interactions.

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. Methods In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen ® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Results Areas under the concentration–time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations ( C max ) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80–1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max ( t max ) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INR max ); however, a 2% increase in area under the INR curve (AUC INR ) was observed. Conclusions Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen ® are recommended when coadministered with dulaglutide. Clinical trial registration numbers NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Empagliflozin is a sodium glucose cotransporter 2 inhibitor in clinical development as a treatment for type 2 diabetes mellitus. The goal of this study was to investigate potential drug–drug interactions between empagliflozin and verapamil, ramipril, and digoxin in healthy volunteers. The potential drug–drug interactions were evaluated in 3 separate trials. In the first study, 16 subjects were randomized to receive single-dose empagliflozin 25 mg alone or single-dose empagliflozin 25 mg with single-dose verapamil 120 mg. In the second study, 23 subjects were randomized to receive empagliflozin 25 mg once daily (QD) for 5 days, ramipril (2.5 mg on day 1 then 5 mg QD on days 2–5) for 5 days or empagliflozin 25 mg with ramipril (2.5 mg on day 1 then 5 mg QD on days 2–5) for 5 days. In the third study, 20 subjects were randomized to receive single-dose digoxin 0.5 mg alone or empagliflozin 25 mg QD for 8 days with single-dose digoxin 0.5 mg on day 5. Exposure of empagliflozin was not affected by coadministration with verapamil (AUC0–∞: geometric mean ratio [GMR], 102.95%; 90% CI, 98.87–107.20; Cmax: GMR, 92.39%; 90% CI, 85.38–99.97) or ramipril (AUC over a uniform dosing interval τ at steady state [AUCτ,ss]: GMR, 96.55%; 90% CI, 93.05–100.18; Cmax at steady state [Cmax,ss]: GMR, 104.47%; 90% CI 97.65–111.77). Empagliflozin had no clinically relevant effect on exposure of ramipril (AUCτ,ss: GMR, 108.14%; 90% CI 100.51–116.35; Cmax,ss: GMR, 103.61%; 90% CI, 89.73–119.64) or its active metabolite ramiprilat (AUCτ,ss: GMR, 98.67%; 90% CI, 96.00–101.42; Cmax,ss: GMR, 98.29%; 90% CI, 92.67–104.25). Coadministration of empagliflozin had no clinically meaningful effect on digoxin AUC0–∞ (GMR, 106.11%; 90% CI, 96.71–116.41); however, a slight increase in Cmax was observed that was not considered clinically relevant (GMR, 113.94%; 90% CI, 99.33–130.70). All treatments were well tolerated. There were no serious adverse events or adverse events leading to discontinuation in any of the studies. No dose adjustment of empagliflozin is required when coadministered with ramipril or verapamil, and no dose adjustment of digoxin or ramipril is required when coadministered with empagliflozin. ClinicalTrials.gov identifiers: NCT01306175 (digoxin), NCT01276301 (verapamil), and NCT01284621 (ramipril).

Purpose Ticagrelor is a reversibly binding P2Y 12 receptor antagonist for the prevention of atherothrombotic events in patients with acute coronary syndrome. Previous in vitro studies showed that ticagrelor is a substrate and inhibitor of P-glycoprotein (ABCB1). Therefore, we examined the potential interaction between digoxin, a P-glycoprotein substrate, and ticagrelor by evaluating the pharmacokinetics, safety, and tolerability. Methods This was a randomized, double-blind, two-period crossover study in healthy volunteers ( n  = 20). Pharmacokinetic parameters of digoxin and ticagrelor were evaluated following co-administration of ticagrelor 400 mg qd or placebo on days 1–16, and digoxin (0.25 mg bid on day 6 and 0.25 mg qd on days 7–14). Results Co-administration of ticagrelor increased the digoxin maximum plasma concentration by 75 %, from 1.8 ng/ml to 3.0 ng/ml (Gmean ratio [GMR] 1.75 [95 % CI, 1.52–2.01]); minimum plasma concentration by 31 %, from 0.5 ng/ml to 0.7 ng/ml (GMR 1.31, 1.13–1.52); and mean area under the curve by 28 %, from 16.8 ng · h/ml to 21.0 ng · h/ml (GMR 1.28, 1.12–1.46), compared with placebo. Renal clearance of digoxin was unaffected by the presence of ticagrelor. Digoxin had no effect on the pharmacokinetics of ticagrelor or its active metabolite, AR-C124910XX. Co-administration of ticagrelor and digoxin was well tolerated. Conclusions Collectively, these results indicate that ticagrelor is a weak inhibitor of the P-glycoprotein transporter. Based on these findings, it is recommended that serum concentrations of drugs like digoxin (P-glycoprotein transporter substrates with a narrow therapeutic range) are monitored when initiating or changing ticagrelor therapy.

Background The novel iron-based phosphate binder sucroferric oxyhydroxide is being investigated for the treatment of hyperphosphatemia. Patients with chronic kidney disease often have multiple comorbidities that may necessitate the daily use of several types of medication. Therefore, the potential pharmacokinetic drug–drug interactions between sucroferric oxyhydroxide and selected drugs commonly taken by dialysis patients were investigated. Methods Five Phase I, single-center, open-label, randomized, three-period crossover studies in healthy volunteers investigated the effect of a single dose of sucroferric oxyhydroxide 1 g (based on iron content) on the pharmacokinetics of losartan 100 mg, furosemide 40 mg, omeprazole 40 mg, digoxin 0.5 mg and warfarin 10 mg. Pharmacokinetic parameters [including area under the plasma concentration–time curve (AUC) from time 0 extrapolated to infinite time (AUC 0–∞ ) and from 0 to 24 h (AUC 0–24 )] for these drugs were determined: alone in the presence of food; with sucroferric oxyhydroxide in the presence of food; 2 h after food and sucroferric oxyhydroxide administration. Results Systemic exposure based on AUC 0–∞ for all drugs, and AUC 0–24 for all drugs except omeprazole (for which AUC 0–8 h was measured), was unaffected to a clinically significant extent by the presence of sucroferric oxyhydroxide, irrespective of whether sucroferric oxyhydroxide was administered with the drug or 2 h earlier. Conclusions There is a low risk of drug–drug interactions between sucroferric oxyhydroxide and losartan, furosemide, digoxin and warfarin. There is also a low risk of drug–drug interaction with omeprazole (based on AUC 0–∞ values). Therefore, sucroferric oxyhydroxide may be administered concomitantly without the need to adjust the dosage regimens of these drugs.

Background Recent data suggest that P-glycoprotein may be involved in cellular transport of lacosamide. Objective To investigate potential drug–drug interactions (DDIs) between lacosamide and digoxin, this phase I, multiple-dose, randomised, double-blind, placebo-controlled, crossover trial assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of digoxin administered in combination with lacosamide or placebo. Methods Twenty healthy White male volunteers were randomised. After receiving digoxin 0.25 mg three times daily on day 1 (loading dose), participants received digoxin 0.25 mg once daily on days 2–22. Participants received either lacosamide (200 mg twice daily) or placebo on days 8–11 and vice versa on days 18–21, after a 6-day washout. The steady-state area under concentration–time curve over the dosing interval (AUC 24,ss ) and maximum steady-state plasma concentration ( C max,ss ) of digoxin were measured; ratios of these parameters for co-administration of digoxin + lacosamide versus digoxin alone were used to evaluate potential DDIs. Interaction was excluded if the 90 % confidence interval (CI) for the geometric mean ratio of AUC 24,ss and C max,ss fell within the acceptance range for bioequivalence (0.8–1.25). Results The point estimates (90 % CI) of the geometric mean ratios for co-administration of digoxin with lacosamide versus digoxin alone for AUC 24,ss [1.024 (0.979–1.071)] and C max,ss [1.049 (0.959–1.147)] were within the acceptance range for bioequivalence. Digoxin and lacosamide co-administration was generally well-tolerated. A small numerical increase in the mean PR interval following co-administered digoxin + lacosamide was observed versus digoxin alone and versus pre-treatment baseline values (178.5 vs. 170.4 or 166.8 ms, respectively). The RR interval increased in parallel. The change was not considered clinically relevant. Conclusion Co-administration of steady-state digoxin (0.25 mg/day) with multiple-dose lacosamide (400 mg/day) versus digoxin alone revealed no differences in digoxin disposition.

Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.

To investigate the impact of the direct Factor Xa inhibitor darexaban administered in a modified-release formulation (darexaban-MR) on the pharmacokinetic (PK) profile of digoxin. In this Phase I, randomized, double-blind, two-period crossover study (8 days for each treatment, 10 days washout), 24 healthy subjects received darexaban-MR 120 mg once/day (qd) + digoxin 0.25 mg qd in one treatment period, and placebo + digoxin 0.25 mg qd in the other treatment period. Blood for PK assessment of digoxin and darexaban was obtained in serial profile on day 8, as well as pre-dose on day 6–7; urinary PK samples were obtained up to 24 h after the last dose on day 8. A lack of interaction was determined if 90 % confidence intervals (CIs) for the geometric mean ratios (GMR) of digoxin Cmax,ss and AUC0–24h,ss with and without darexaban-MR co-administration were within 0.80–1.25 limits. Pharmacodynamic activity was assessed by international normalized ratio and activated partial thromboplastin time. Twenty-three subjects completed the study. The GMR (90 % CI) for Cmax,ss and AUC0–24h,ss of digoxin plus darexaban versus digoxin plus placebo was 1.03 (90 % CI: 0.94–1.12) and 1.11 (90 % CI: 1.05–1.17), respectively. The 90 % CI for the GMRs fell within the limits of 0.80–1.25, indicating a lack of drug–drug interaction. Co-administration of digoxin with darexaban-MR was well tolerated, with no unexpected treatment-emergent adverse events or safety concerns. Co-administration of darexaban-MR did not impact the steady-state PK profile of digoxin.