Aims
The anticoagulant rivaroxaban is an oral, direct Factor Xa inhibitor for the management of thromboembolic disorders. Metabolism and excretion involve cytochrome P450 3A4 (CYP3A4) and 2J2 ...(CYP2J2), CYP‐independent mechanisms, and P‐glycoprotein (P‐gp) and breast cancer resistance protein (Bcrp) (ABCG2).
Methods
The pharmacokinetic effects of substrates or inhibitors of CYP3A4, P‐gp and Bcrp (ABCG2) on rivaroxaban were studied in healthy volunteers.
Results
Rivaroxaban did not interact with midazolam (CYP3A4 probe substrate). Exposure to rivaroxaban when co‐administered with midazolam was slightly decreased by 11% (95% confidence interval CI −28%, 7%) compared with rivaroxaban alone. The following drugs moderately affected rivaroxaban exposure, but not to a clinically relevant extent: erythromycin (moderate CYP3A4/P‐gp inhibitor; 34% increase 95% CI 23%, 46%), clarithromycin (strong CYP3A4/moderate P‐gp inhibitor; 54% increase 95% CI 44%, 64%) and fluconazole (moderate CYP3A4, possible Bcrp ABCG2 inhibitor; 42% increase 95% CI 29%, 56%). A significant increase in rivaroxaban exposure was demonstrated with the strong CYP3A4, P‐gp/Bcrp (ABCG2) inhibitors (and potential CYP2J2 inhibitors) ketoconazole (158% increase 95% CI 136%, 182% for a 400 mg once daily dose) and ritonavir (153% increase 95% CI 134%, 174%).
Conclusions
Results suggest that rivaroxaban may be co‐administered with CYP3A4 and/or P‐gp substrates/moderate inhibitors, but not with strong combined CYP3A4, P‐gp and Bcrp (ABCG2) inhibitors (mainly comprising azole‐antimycotics, apart from fluconazole, and HIV protease inhibitors), which are multi‐pathway inhibitors of rivaroxaban clearance and elimination.
Adverse cardiac remodeling is a major risk factor for the development of post myocardial infarction (MI) heart failure (HF). This study investigates the effects of the chymase inhibitor fulacimstat ...on adverse cardiac remodeling after acute ST-segment-elevation myocardial infarction (STEMI).
In this double-blind, randomized, placebo-controlled trial patients with first STEMI were eligible. To preferentially enrich patients at high risk of adverse remodeling, main inclusion criteria were a left-ventricular ejection fraction (LVEF) ≤45% and an infarct size >10% on day 5 to 9 post MI as measured by cardiac MRI. Patients were then randomized to 6 months treatment with either 25 mg fulacimstat (n = 54) or placebo (n = 53) twice daily on top of standard of care starting day 6 to 12 post MI. The changes in LVEF, LV end-diastolic volume index (LVEDVI), and LV end-systolic volume index (LVESVI) from baseline to 6 months were analyzed by a central blinded cardiac MRI core laboratory.
Fulacimstat was safe and well tolerated and achieved mean total trough concentrations that were approximately tenfold higher than those predicted to be required for minimal therapeutic activity. Comparable changes in LVEF (fulacimstat: 3.5% ± 5.4%, placebo: 4.0% ± 5.0%, P = .69), LVEDVI (fulacimstat: 7.3 ± 13.3 mL/m2, placebo: 5.1 ± 18.9 mL/m2, P = .54), and LVESVI (fulacimstat: 2.3 ± 11.2 mL/m2, placebo: 0.6 ± 14.8 mL/m2, P = .56) were observed in both treatment arms.
Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on cardiac remodeling.
Aim
Regorafenib is a multikinase inhibitor under investigation for use in neovascular age‐related macular degeneration. In this phase I study, regorafenib eye drops were administered to healthy ...volunteers to provide information on safety, tolerability and systemic exposure.
Methods
This was a single‐centre, randomized, double‐masked, parallel‐group, dose‐escalation, placebo‐controlled study. Subjects received regorafenib eye drops (30 mg ml−1, 25 μl) as a 0.75 mg single dose (Cohort 1), 0.75 mg twice daily (bid) or thrice daily (tid) over 14 days (Cohorts 2 and 3, respectively), 1.5 mg tid unilaterally for 3 days, then bilaterally for up to 14 days (Cohort 4), or placebo. Plasma samples were taken to estimate systemic exposure. Safety and functional assessments were performed throughout the study.
Results
Thirty‐six subjects received regorafenib and 12 received placebo. Regorafenib was safe and well tolerated over the dose range. No pathological changes occurred in the anterior, vitreous or posterior eye compartments. Mild eyelid redness, oedema and conjunctival hyperaemia were observed across all regorafenib cohorts; these were comparable with the effects seen with placebo. Predominant symptoms were blurred vision in the active and placebo groups. Systemic safety evaluations showed no clinically relevant findings. Absolute systemic exposure after multiple administrations of regorafenib eye drops at a dose of 0.75 mg was 600–700‐fold lower than after multiple oral administration of 160 mg day−1, the dose approved in cancer indications.
Conclusion
These results indicate a favourable safety and tolerability profile of regorafenib eye drops up to 30 mg ml−1 tid for use in clinical studies.
The EINSTEIN-Jr program will evaluate rivaroxaban for the treatment of venous thromboembolism (VTE) in children, targeting exposures similar to the 20 mg once-daily dose for adults.
This was a ...multinational, single-dose, open-label, phase I study to describe the pharmacodynamics (PD), pharmacokinetics (PK) and safety of a single bodyweight-adjusted rivaroxaban dose in children aged 0.5-18 years. Children who had completed treatment for a venous thromboembolic event were enrolled into four age groups (0.5-2 years, 2-6 years, 6-12 years and 12-18 years) receiving rivaroxaban doses equivalent to 10 mg or 20 mg (either as a tablet or oral suspension). Blood samples for PK and PD analyses were collected within specified time windows.
Fifty-nine children were evaluated. In all age groups, PD parameters (prothrombin time, activated partial thromboplastin time and anti-Factor Xa activity) showed a linear relationship versus rivaroxaban plasma concentrations and were in line with previously acquired adult data, as well as in vitro spiking experiments
The rivaroxaban pediatric physiologically based pharmacokinetic model, used to predict the doses for the individual body weight groups, was confirmed. No episodes of bleeding were reported, and treatment-emergent adverse events occurred in four children and all resolved during the study.
Bodyweight-adjusted, single-dose rivaroxaban had predictable PK/PD profiles in children across all age groups from 0.5 to 18 years. The PD assessments based on prothrombin time and activated partial thromboplastin time demonstrated that the anticoagulant effect of rivaroxaban was not affected by developmental hemostasis in children.
ClinicalTrials.gov number, NCT01145859.
Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. Unwanted pro-arrhythmic effects ...are a common reason for drugs failing to gain regulatory approval; these properties can be detected by assessing the effect of the drug on the QT interval.
This study was performed, in accordance with International Conference on Harmonisation (ICH) E14 guidance, to assess whether rivaroxaban prolongs the QT interval.
This was a prospective, randomized, double-blind, double-dummy, four-way crossover study.
The study was conducted at a clinical pharmacology research unit.
Healthy male and female subjects (n = 54) aged > or =50 years were enrolled and remained in the study unit for 3 days for each treatment. Of these, 50 patients were eligible for the QT analysis.
Subjects received single oral doses of rivaroxaban 45 mg or 15 mg, moxifloxacin 400 mg (positive control), or placebo.
Multiple ECGs were taken at frequent intervals after drug administration, and the QT interval was measured manually under blinded conditions at a central laboratory. The Fridericia correction formula (QTcF) was used to correct the QT interval for heart rate. The primary outcome was the effect of rivaroxaban or moxifloxacin on the placebo-subtracted QTcF 3 hours after administration. The frequency of outlying QTcF values and the tolerability of the treatments were also assessed.
All treatments were well tolerated and had no effect on heart rate. Moxifloxacin established the required assay sensitivity; placebo-subtracted QTcF 3 hours after moxifloxacin administration was prolonged by 9.77 ms (95% CI 7.39, 12.15). Placebo-subtracted QTcF values 3 hours after rivaroxaban administration were -0.91 ms (95% CI -3.33, 1.52) and -1.83 ms (95% CI -4.19, 0.54) with rivaroxaban 45 mg and 15 mg, respectively. QTcF was not prolonged with rivaroxaban at any time, and the frequency of outlying results with rivaroxaban and placebo was similar.
This thorough QT study, which was performed in accordance with ICH E14 guidelines, shows that rivaroxaban does not prolong the QTc interval. Therefore, the potential of rivaroxaban for the prevention and treatment of thromboembolic disorders, including chronic cardiovascular disorders, can be investigated in appropriate clinical studies without the need for intensive monitoring of the QTc interval.
The orally available chymase inhibitor BAY 1142524 is currently being developed as a first‐in‐class treatment for left‐ventricular dysfunction after myocardial infarction. Results from 3 randomized, ...single‐center, phase 1 studies in healthy male volunteers examining the safety, tolerability, and pharmacokinetics of BAY 1142524 are summarized. In this first‐in‐human study, single oral doses of 1‐200 mg were administered in fasted state as liquid service formulation or immediate release (IR) tablets. The relative bioavailability and the effect of a high‐fat/high‐calorie meal were investigated at the 5‐mg dose. In a multiple‐dose escalation study, doses of 5‐50 mg twice daily and 100 mg once daily were given for 5 consecutive days. BAY 1142524 was safe and well tolerated and had no effects on heart rate or blood pressure compared with placebo. BAY 1142524 was absorbed with peak concentration 1‐3 hours after administration for IR tablets; it was eliminated from plasma with a terminal half‐life of 6.84‐12.0 hours after administration of liquid service formulation or IR tablets. Plasma exposures appeared to be dose‐linear, with a negligible food effect. There was only low accumulation of BAY 1142524 after multiple dosing. BAY 1142524 exhibited a pharmacokinetic profile allowing for once‐daily dosing. The absence of blood pressure effects after administration of BAY 1142524 supports the combination of this novel anti‐remodeling drug with existing standard of care in patients with left‐ventricular dysfunction after acute myocardial infarction.
Rivaroxaban, an oral, direct factor Xa inhibitor, is currently used in clinical practice for the prevention and treatment of thromboembolic disorders. This single‐center, three‐way crossover study ...was designed to investigate the pharmacodynamic effects of rivaroxaban (10 mg) and enoxaparin (40 mg) alone and in combination as well as the influence of enoxaparin on the pharmacokinetics of rivaroxaban in healthy male subjects. When given alone, both drugs exhibited similar, rapid anti‐factor Xa activity. Combined administration resulted in an increase of ∼50% in anti‐factor Xa activity and a lesser increase in activated partial thromboplastin time, compared with either drug alone. Enoxaparin had no additional effect on prolongation of the prothrombin time induced by rivaroxaban and did not affect the pharmacokinetic parameters of rivaroxaban. The results showed that rivaroxaban (10 mg) and enoxaparin (40 mg) had a similar and rapid onset of action, as indicated by the similar anti‐factor Xa activity–time curves, suggesting that both drugs have a similar duration of pharmacological activity at the factor X site. Co‐administration of rivaroxaban and enoxaparin is associated with enhanced pharmacodynamic effects.
Dual antiplatelet therapy with acetylsalicylic acid and a thienopyridine, such as clopidogrel, is effective for the secondary prevention of cardiovascular events in patients with acute coronary ...syndrome, but there is still a substantial residual risk of recurrence. Although anticoagulant therapy with a vitamin K antagonist (e.g. warfarin) in conjunction with antiplatelet therapy has been shown to reduce the risk of cardiovascular events, the rates of bleeding were increased with these combination therapies; hence, triple therapy with warfarin is currently only recommended in patients at low risk of bleeding. In addition, there are other limitations associated with vitamin K antagonist therapy, including the need for routine coagulation monitoring and dose adjustment to maintain the treatment within the therapeutic range. Rivaroxaban is an oral, direct Factor Xa inhibitor; in clinical practice, it is likely that rivaroxaban will be given to patients who also receive antiplatelet therapy, such as clopidogrel. This randomized, non-blinded, three-way crossover study investigated the effect of rivaroxaban on bleeding time when co-administered with clopidogrel. In addition, the influence of clopidogrel on the safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban was investigated. Of 27 healthy male subjects who received a single 300 mg dose of clopidogrel, 14 were identified as clopidogrel responders and were then randomized to the following three treatments: (A) two doses of clopidogrel on two consecutive days (300 mg on day 1; 75 mg on day 2); (B) one dose of rivaroxaban (15 mg); or (C) a combination of treatments A and B (rivaroxaban given on day 2). All treatments were well tolerated. Bleeding time with co-administration of rivaroxaban and clopidogrel was significantly prolonged in four subjects, compared with either drug alone: combination treatment increased the overall least squares-means to 3.77 times baseline (90% confidence interval CI 2.82-4.73), compared with 1.13 times baseline (90% CI 0.17-2.09) with rivaroxaban and 1.96 times baseline (90% CI 0.10-2.91) with clopidogrel. Co-administration of clopidogrel had no significant effect on the pharmacokinetics of rivaroxaban and, when compared with rivaroxaban alone, had no further effects on Factor Xa activity or prothrombin time. Inhibition of ADP-stimulated platelet aggregation by clopidogrel was not affected by rivaroxaban. As expected, owing to the mode of action of each study drug, the results of this study demonstrated that co-administration of the Factor Xa inhibitor rivaroxaban and the antiplatelet clopidogrel increased the bleeding time in healthy subjects without affecting other pharmacokinetic or pharmacodynamic parameters of each drug.
Aim
This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor.
Method
This ...single centre, non‐randomized, non‐blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child–Pugh classification, and gender‐matched healthy subjects (n = 16).
Results
Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration–time curve (AUC). The least‐squares (LS)‐mean values for AUC were 1.15‐fold 90% confidence interval (CI) 0.85, 1.57 and 2.27‐fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect–time curve and the maximum effect were observed, with LS‐mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment.
Conclusion
Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects.
Background and Objective
There is a clinical need for new oral anticoagulants to prevent and treat thromboembolic diseases. Given its integral role in the coagulation cascade, factor Xa is a ...particularly promising target for new anticoagulation therapies. The aim of this study was to investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939, an oral, direct factor Xa inhibitor.
Methods
This single–center, randomized, single–blinded, placebo–controlled, dose–escalation study included 108 healthy white male subjects aged 19 to 45 years. Subjects received single oral doses of either BAY 59–7939 (1.25–80 mg) or placebo; in addition, 1 group received 2 doses of BAY 59–7939 (5–mg tablet and oral solution) or placebo in a crossover design.
Results
Oral BAY 59–7939 in single doses up to 80 mg was safe and well tolerated and was not associated with an increased risk of bleeding compared with placebo. Pharmacodynamic effects (inhibition of factor Xa activity, prothrombin time, activated partial thromboplastin time, and HepTest) and plasma concentration profiles were dose–dependent. Maximum inhibition of factor Xa activity was achieved 1 to 4 hours after administration of BAY 59–7939 and ranged from 20% to 61% for the 5– to 80–mg doses. BAY 59–7939 selectively inhibited factor Xa activity; thrombin (factor IIa) and antithrombin were unaffected. Inhibition of factor Xa activity and prolongation of prothrombin time correlated well with BAY 59–7939 plasma concentrations (r = 0.949 and 0.935, respectively).
Conclusions
BAY 59–7939 was well tolerated with predictable pharmacodynamics and pharmacokinetics across a wide range of doses in healthy male subjects. BAY 59–7939 was shown to be an effective and specific factor Xa inhibitor.
Clinical Pharmacology & Therapeutics (2005) 78, 412–421; doi: 10.1016/j.clpt.2005.06.011
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