The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous ...thromboembolism. This study investigated the reversal of edoxaban's effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC).
This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban's effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume.
The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation.
http://www.clinicaltrials.gov. Unique identifier: NCT02047565.
Of the new direct oral anticoagulants, direct factor Xa inhibitors are limited by the absence of a proven reversal agent. We assessed the safety, tolerability and impact on anticoagulation reversal ...of ciraparantag (PER977) alone and following a 60 mg dose of the FXa inhibitor edoxaban. Escalating, single IV doses of ciraparantag were administered alone and following a 60 mg oral dose of edoxaban in a double-blind, placebo-controlled fashion to healthy subjects. Serial assessments of the pharmacokinetics and pharmacodynamic effects of ciraparantag were performed. Eighty male subjects completed the study. Following edoxaban (60 mg), a single IV dose of ciraparantag (100 to 300 mg) demonstrated full reversal of anticoagulation within 10 minutes and sustained for 24 hours. Fibrin diameter within clots was restored to normal 30 minutes after a single dose of 100 to 300 mg ciraparantag as determined by scanning electron microscopy and change in fibrin diameter quantified by automated image analysis. Potentially related adverse events were periorbital and facial flushing and cool sensation following IV injection of ciraparantag. Renal excretion of ciraparantag metabolite was the main elimination route. There was no evidence of procoagulant activity following ciraparantag as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels. In conclusion, ciraparantag in healthy subjects is safe and well tolerated with minor, non-dose limiting adverse events. Baseline haemostasis was restored from the anticoagulated state with doses of 100 to 300 mg ciraparantag within 10-30 minutes of administration and sustained for at least 24 hours.
Edoxaban is an oral, direct, once-daily, factor Xa inhibitor developed for stroke prevention in patients with atrial fibrillation and for the treatment and secondary prevention of recurrent ...thromboembolism in patients with acute symptomatic venous thromboembolism. Among elderly patients who require anticoagulation therapies, some may have end-stage renal disease (ESRD). This open-label, phase 1, randomised, two-way crossover study was conducted to evaluate the pharmacokinetics of edoxaban in 10 subjects on haemodialysis. Eligible subjects with ESRD on chronic haemodialysis received a single, oral dose of edoxaban 15 mg 2 hours (h) prior to (on-dialysis) or in between (off-dialysis) haemodialysis sessions. Haemodialysis resulted in a minor decrease in mean total exposure (AUC0-∞; 676.2 ng·h/ml) as compared with that observed in subjects off-dialysis (691.7 ng·h/ml). Mean maximum observed plasma concentration (Cmax) values were comparable between on-dialysis and off-dialysis treatments (53.3 vs 56.3 ng/ml, respectively). Mean apparent total body clearance (CL/F) values were 24.1 and 22.5 l/h during the on-dialysis and off-dialysis treatment periods, respectively. Dialyser clearance was 5.7 l/h and haemodialysis clearance was 6.1 l/h. Haemodialysis clearance was only 6.1 l/h, suggesting that it only accounts for one-fourth of the total clearance in these subjects. A single, oral dose of 15 mg of edoxaban was well tolerated by subjects with ESRD. In conclusion, based on these single-dose PK data, a supplementary dose of edoxaban may not be required following a haemodialysis session. Importantly, haemodialysis is not an effective mechanism for removal of edoxaban from the blood.
Mirogabalin is a novel, preferentially selective α2δ‐1 ligand under investigation to treat neuropathic pain. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics ...of various doses of mirogabalin in healthy subjects of different ethnicities. This randomized, placebo‐controlled, double‐blind, sequential, ascending‐dose study evaluated single (10‐40 mg) and repeated (10, 15 mg twice a day) doses of mirogabalin in Japanese subjects, and a single dose of mirogabalin in Korean, Chinese, and white subjects. Mirogabalin was rapidly absorbed, with a median time to maximum plasma concentration of 1 hour, and rapidly eliminated, with a mean elimination half‐life of 2 to 3 hours. Single‐dose mirogabalin pharmacokinetic parameters were comparable between Asian and white subjects. Exposure increased proportionally as mirogabalin dose increased in Japanese subjects. Mean mirogabalin steady‐state clearance and volume of distribution values were comparable across dose levels. No accumulation of mirogabalin was observed on repeated dosing in Japanese subjects. Mirogabalin had an acceptable safety and tolerability profile in Asian and white subjects at doses up to 15 mg twice a day for 7 days. The most common treatment‐emergent adverse events (somnolence, headache, and dizziness) were consistent with the known mechanism of action and safety profile of mirogabalin.
The COVID‐19 pandemic has forced clinical studies to accommodate imposed limitations. In this study, the bioequivalence part could not be conducted as planned. Thus, the aim was to demonstrate ...bioequivalence, using an adaptive study design, of tadalafil in fixed‐dose combination (FDC) tablets of macitentan/tadalafil with single macitentan and tadalafil (Canadian‐sourced) tablets and assess the effect of food on FDC tablets in healthy subjects. This Phase 1, single‐center, open‐label, single‐dose, two‐part, two‐period, randomized, crossover study enrolled 62 subjects. Tadalafil bioequivalence as part of FDC of macitentan/tadalafil (10/40 mg) with single‐component tablets of macitentan (10 mg) and tadalafil (40 mg) was determined by pharmacokinetic (PK) assessment under fasted conditions. The effect of food on FDC was evaluated under fed and fasted conditions. Fasted 90% confidence intervals (CIs) for geometric mean ratios (GMRs) were within bioequivalence limits for tadalafil and macitentan. Fed and fasted 90% CIs for area under the curve (AUC) GMR were within bioequivalence limits. However, 90% CIs for maximum plasma concentration (Cmax) GMR for macitentan and tadalafil were outside bioequivalence limits. One FDC‐treated subject experienced a serious adverse event of transient ischemic attack (bioequivalence part). To address pandemic‐imposed limitations, an adaptive study design was implemented to demonstrate that the FDC tablet was bioequivalent to the free combination of macitentan and tadalafil (Canadian‐sourced). No clinically significant differences in PK were determined between fed and fasted conditions; the FDC formulation could be taken irrespective of meals. The FDC formulation under fasted and fed conditions was well tolerated with no clinically relevant differences in safety profiles between the treatment groups.
NCT Number: NCT04235270.
The macitentan 10 mg/tadalafil 40 mg Fixed Dose Combination is bioequivalent to the free combination. No clinically significant differences in PK were determined between fed and fasted conditions of the FDC formulation.
Three phase 1 pharmacokinetic (PK)/pharmacodynamics (PD) studies were conducted in healthy men and women to further characterize the safety, tolerability, and PK/PD of mirogabalin administration with ...or without food and to guide the dose selection and regimen for phase 2 and 3 clinical development. The 3 studies included 2 randomized, double‐blind, placebo‐controlled, single‐ and multiple‐ascending‐dose studies, and 1 open‐label, crossover study to evaluate the PK of mirogabalin administered under fasting and fed (high‐fat meal) conditions. Forty‐eight and 47 healthy volunteers completed the single‐ and multiple‐dose studies, respectively. Thirty subjects were enrolled and completed the food effect study. Mirogabalin was well tolerated in the fed and fasted states. The most frequent treatment‐emergent adverse events (TEAEs)—dizziness and somnolence—were expected based on mirogabalin's mechanism of action. Subjects receiving the highest mirogabalin doses (50 and 75 mg single dose) showed greater dizziness and sedation and higher rates of TEAEs than subjects receiving 3‐30 mg. After oral administration, mirogabalin was rapidly absorbed (time to maximum concentration, ∼1 hour) and eliminated through urine unchanged (61%‐72% urinary excretion). Exposure increased in a dose‐proportional manner after single or multiple mirogabalin doses. No significant accumulation occurred with multiple doses over 14 days. After single doses of mirogabalin (15 mg), the bioavailability was considered equivalent in the fed and fasted states, indicating that mirogabalin can be taken without food restrictions. Based on these data, mirogabalin 15 mg twice daily was selected as the highest target dose for further clinical development.
MK-5046 is an orally active, potent, selective agonist of the orphan G protein–coupled receptor bombesin receptor subtype-3 (BRS-3) that is under evaluation for treatment of obesity. We report the ...safety, tolerability, pharmacokinetics, and pharmacodynamics of oral doses of MK-5046 (10-160 mg) in a double-blind, randomized, placebo-controlled study in healthy and obese male volunteers. MK-5046 exposure increased dose proportionally, and MK-5046 was eliminated with an apparent terminal half-life of 1.5 to 3.5 hours. Single doses transiently increased blood pressure. Patients reported adverse events (erections and feeling hot, cold, and/or jittery) that coincided with time of occurrence (Tmax) and increased with increasing dose. No changes were observed in body temperature, heart rate, plasma glucose levels, or feelings of hunger/satiety. The blood pressure and thermal experiences attenuated with a second dose 6 hours after the first. Additionally, the erections suggest a possible, unanticipated, role for BRS-3 in reproductive physiology. Oral administration of MK-5046 achieves plasma concentrations that are projected to activate BRS-3 and therefore should be suitable for exploring its biological role in humans.
The effect of N-acetylcysteine on renal function, nitric oxide, and oxidative stress after angiography.
Renal failure induced by radiographic contrast agents is a known complication of coronary ...angiography, especially among patients with chronic renal failure. Recently, treatment with N-acetylcysteine (NAC) has been shown to have a protective effect but the mechanisms are unknown. We examined the hypothesis that NAC protected against contrast-induced renal impairment through effects on nitric oxide metabolism and oxidative stress.
Patients with a serum creatinine concentration above 106 μmol/L undergoing coronary angiography were randomly assigned to receive either NAC 1g (N = 24) or placebo (N = 29) twice daily 24hours before and after angiography with 0.45% saline hydration in a double-blind study. Creatinine clearance was calculated and urinary nitric oxide and F2-isoprostane excretion were measured at baseline, 24 and 96hours after angiography.
Treatment with NAC significantly improved the effect of contrast media on creatinine clearance, and maximal beneficial effect was observed 24hours after angiography. Creatinine clearance (mL/min) was 59.5 ± 4.4, 64.7 ± 5.8, and 58.7+3.9 at baseline, 24, and 96hours after angiography in the NAC group, respectively, and 65.2 ± 3.2, 51.5 ± 3.7, and 53.6 ± 3.9 in the placebo group, respectively (P < 0.0001). NAC treatment prevented the reduction in urinary nitric oxide after angiography. The urinary nitric oxide/creatinine ratio (μmol/mg) was 0.0058 ± 0.0004, 0.0057 ± 0.0004, and 0.0052 ± 0.0004 at baseline, 24, and 96hours after angiography in NAC group, respectively, and 0.0057 ± 0.0007, 0.0031 ± 0.0005, and 0.0039 ± 0.0005 in the placebo group, respectively (P = 0.013). NAC had no significant effect on urinary F2-isoprostanes.
NAC treatment has renoprotective effect in patients with mild chronic renal failure undergoing coronary angiography that may be mediated in part by an increase in nitric oxide production.
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