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Background The protease chymase generates multiple factors involved in tissue remodelling including angiotensin II (Ang II) and has been implicated in the pathophysiology of diabetic kidney disease (DKD). This study investigated the effects of the chymase inhibitor fulacimstat on albuminuria in patients with Type II diabetes mellitus and a clinical diagnosis of DKD. Methods In this double-blind, randomized, placebo-controlled trial, patients were on the maximum tolerated dose of either an Ang II receptor blocker or an Ang-converting enzyme inhibitor since at least 3 months before the screening visit. Eligible patients were randomized in a 2:1 ratio to treatment with either 25 mg fulacimstat (n = 99) or placebo (n = 48) twice daily on top of standard of care. Results The randomized patients had a mean urine albumin–creatinine ratio (UACR) of 131 mg/g (range: 29–2429 mg) and a mean (standard deviation) estimated glomerular filtration rate of 60.8 ± 16.9 mL/min/1.73 m2 before treatment start. Fulacimstat was safe and well tolerated, and achieved mean total trough concentrations that were ∼9-fold higher than those predicted to be required for minimal therapeutic activity. UACR increased by 27.4% [coefficient of variation (CV) 86%] and 3% (CV 88.9%) after 24 weeks of treatment with placebo or fulacimstat, respectively. Analysis of covariance revealed a least square mean UACR ratio (fulacimstat/placebo) of 0.804 (90% CI 0.627–1.030, P = 0.1477), indicating a statistically non-significant UACR reduction of 19.6% after fulacimstat treatment compared with placebo. Conclusions Fulacimstat was safe and well tolerated but did not reduce albuminuria in patients with DKD. These findings do not support a therapeutic role for chymase inhibition in DKD.

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.

Essentials In this crossover study the anticoagulant effects of rivaroxaban and apixaban were compared. Healthy volunteers received rivaroxaban 20 mg once daily or apixaban 5 mg twice daily. Rivaroxaban was associated with more prolonged inhibition of thrombin generation than apixaban. Rivaroxaban induced a clear prolongation of prothrombin time and activated partial thromboplastin time. SummaryBackground The anticoagulant actions of the oral direct activated factor Xa inhibitors, rivaroxaban and apixaban, have not previously been directly compared. Objectives To compare directly the steady-state pharmacokinetics and anticoagulant effects of rivaroxaban and apixaban at doses approved for stroke prevention in patients with non-valvular atrial fibrillation. Methods Twenty-four healthy Caucasian male volunteers were included in this open-label, two-period crossover, phase 1 study (EudraCT number: 2015-002612-32). Volunteers were randomized to receive rivaroxaban 20 mg once daily or apixaban 5 mg twice daily for 7 days, followed by a washout period of at least 7 days before they received the other treatment. Plasma concentrations and anticoagulant effects were measured at steady state and after drug discontinuation. Results Overall exposure was similar for both drugs: the geometric mean area under the plasma concentration–time curve for the 0–24-h interval was 1830 μg h L−1 for rivaroxaban and 1860 μg h L−1 for apixaban. Rivaroxaban was associated with greater inhibition of endogenous thrombin potential (geometric mean area under the curve relative to baseline during the 0–24-h interval: 15.5 h versus 17.5 h) and a more pronounced maximal prolongation relative to baseline of prothrombin time (PT) (1.66-fold versus 1.14-fold) and activated partial thromboplastin time (APTT) (1.43-fold versus 1.16-fold) at steady state than apixaban. Conclusions Despite similar exposure to both drugs, rivaroxaban 20 mg once daily was associated with greater and more sustained inhibition of thrombin generation than apixaban 5 mg twice daily. Sensitive PT and APTT assays can be used to estimate the anticoagulant effects of rivaroxaban.

Introduction Adverse cardiac remodelling represents the most important risk factor for the development of heart failure (HF) after myocardial infarction (MI). Chymase is a protease that generates locally pro-fibrotic factors such as angiotensin II, TGFβ, and matrixmetallproteases that contribute to tissue remodelling. Purpose This phase IIa study examined the effects of the chymase inhibitor fulacimstat on functional parameters of adverse cardiac remodelling after acute MI. Methods A double-blind, multinational, randomized, placebo-controlled study was performed in patients after first STEMI who were treated with primary percutaneous coronary intervention within 24h of symptom onset. To enrich for patients at risk of adverse remodelling, 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. On day 6 to 12 post MI, patients were randomized to treatment with either 25 mg fulacimstat (n=54) or placebo (n=53) twice daily on top of standard of care. The changes in LVEF, LVEDVI, and LVESVI from baseline to 6 months of treatment were analyzed by a central blinded cardiac MRI core laboratory. Results Fulacimstat was safe and well tolerated, 64.8% of patients treated with fulacimstat and 75.5% of patients treated with placebo reported treatment emergent adverse events. Fulacimstat achieved exposures that were approximately 10-fold higher than those predicted to be required for minimal therapeutic activity. After six months of treatment, there were no effects of fulacimstat compared to placebo on the changes in LVEF, LVEDVI, and LVESVI (see Table). Analysis of primary efficacy parameters Parameter Placebo Fulacimstat p-value LVEF (%) baseline 37.2±6.1 39.1±5.5 0.15 6 months 41.2±8.4 42.6±8.4 0.45 delta 4.0±5.0 3.5±5.4 0.69 LVEDVI (mL/m2) baseline 80.0±17.1 77.4±18.2 0.51 6 months 85.1±19.1 84.7±23.4 0.94 delta 5.1±18.9 7.3±13.3 0.54 LVESVI (mL/m2) baseline 50.5±13.0 47.3±12.3 0.26 6 months 51.1±16.9 49.6±18.1 0.71 delta 0.6±14.8 2.3±11.2 0.56 Data are given as mean ± standard deviation. Conclusion Fulacimstat was safe and well tolerated in patients with left-ventricular dysfunction (LVD) after first STEMI but had no effect on adverse cardiac remodelling in the experimental setting of this study. Acknowledgement/Funding The study was funded by its sponsor BAYER AG

Background Rivaroxaban has been shown to be efficacious for treatment of venous thromboembolism in adults, and has a reduced risk of bleeding compared with standard anticoagulants. We aimed to develop paediatric rivaroxaban regimens for the treatment of venous thromboembolism in children and adolescents. Methods In this phase 2 programme, we did three studies to evaluate rivaroxaban treatment in children younger than 6 months, aged 6 months to 5 years, and aged 6-17 years. Our studies used a multicentre, single-arm design at 54 sites in Australia, Europe, Israel, Japan, and north America. We included children with objectively confirmed venous thromboembolism previously treated with low-molecular weight heparin, fondaparinux, or a vitamin K antagonist for at least 2 months or, in children who had catheter-related venous thromboembolism for at least 6 weeks. We administered rivaroxaban orally in a bodyweight-adjusted 20 mg-equivalent dose, based on physiologically-based pharmacokinetic modelling predictions and EINSTEIN-Jr phase 1 data in young adults, in either a once-daily (tablets; for those aged 6-17 years), twice-daily (in suspension; for those aged 6 months to 11 years), or three times-daily (in suspension; for those younger than 6 months) dosing regimen for 30 days (or 7 days for those younger than 6 months). The primary aim was to define rivaroxaban treatment regimens that match the target adult exposure range. The principal safety outcome was major bleeding and clinically relevant non-major bleeding. Analyses were per-protocol. The predefined efficacy outcomes were symptomatic recurrent venous thromboembolism, asymptomatic deterioration on repeat imaging at the end of the study treatment period. These trials are registered at ClinicalTrials.gov, numbers NCT02564718, NCT02309411, and NCT02234843. Findings Between Feb 11, 2013, and Dec 20, 2017, we enrolled 93 children (ten children younger than 6 months; 15 children aged 6 months to 1 year; 25 children aged 2-5 years; 32 children aged 6-11 years; and 11 children aged 12-17 years) into our study. 89 (96%) children completed study treatment (30 days of treatment, or 7 days in those younger than 6 months), and 93 (100%) children received at least one dose of study treatment and were evaluable for the primary endpoints. None of the children had a major bleed, and four (4%, 95% CI 1.2-10.6) of these children had a clinically relevant non-major bleed (three children aged 12-17 years with menorrhagia and one child aged 6-11 years with gingival bleeding). We found no symptomatic recurrent venous thromboembolism in any patients (0%, 0.0-3.9). 24 (32%) of 75 patients with repeat imaging had their thrombotic burden resolved, 43 (57%) patients improved, and eight (11%) patients were unchanged. No patient deteriorated. We confirmed therapeutic rivaroxaban exposures with once-daily dosing in children with bodyweights of at least 30 kg and with twice-daily dosing in children with bodyweights of at least 20 kg and less than 30 kg. Children with low bodyweights (

Background: Gene therapy for hemophilia A has the potential to reduce the treatment burden for care-providers and patients, by eliminating the need for regular factor VIII (FVIII) prophylaxis through the long-term expression of endogenous FVIII at levels sufficient to provide bleed protection. BAY 2599023 (AAVhu37FVIII) is a non-replicating adeno-associated virus (AAV) vector, based on the AAV serotype hu37, which contains a single-stranded DNA genome encoding a B-domain deleted FVIII, under the control of a liver-specific promotor/enhancer combination optimized for transgenic expression. The AAVhu37 capsid is a member of the hepatotropic Clade E family and has been selected based on nonclinical studies demonstrating efficient liver-directed FVIII gene transfer, favorable biodistribution as well as durable FVIII expression. BAY 2599023 is the first clinical-stage AAV gene therapy vector based on the AAVhu37 serotype. This analysis reports safety and FVIII activity following a single intravenous infusion of BAY 2599023 in the first-dose cohort of a phase I/II open-label, first time in human dose-finding study (NCT03588299) of previously treated, severe hemophilia A patients. Patients/Methods: Two participants were enrolled sequentially; each received a single infusion of AAVhu37 (0.5 x 1013 GC/kg). Patients were males ≥18 years with no history of FVIII inhibitor development, no detectable immunity to the AAVhu37 capsid, and >150 exposure days to FVIII products. Primary endpoints were adverse events (AEs), serious AEs and AEs/SAEs of special interest (S/AESI); the secondary endpoint was change in FVIII activity from baseline. Informed patient consent, and ethics committee approval at each local site, were obtained. Results: Following more than 15 weeks of safety observation, no SAEs, AEs related to study drug, nor S/AESI were reported. Liver enzymes (alanine aminotransferase and aspartate aminotransferase) remained Conclusions: BAY 2599023 was previously shown in non-clinical studies to have a good safety profile, with the potential to achieve endogenous expression of FVIII at therapeutic levels, over an extended period of time. In this first-in-human clinical study with BAY 2599023, two patients have been treated with BAY 2599023 at the starting dose of 0.5 x 1013 GC/kg and no safety concerns have been reported to date. Measurable expression of endogenous FVIII and an early read-out of hemostatic efficacy have been demonstrated in both patients. Overall, data generated from this first dose cohort demonstrate that successful translation from pre-clinical to clinical development and proof-of-mechanism for BAY 2599023 was achieved. Disclosures Pipe: HEMA Biologics: Consultancy; Shire: Consultancy; Roche/Genentech: Consultancy; Sanofi: Consultancy; Freeline: Consultancy; Apcintex: Consultancy; Novo Nordisk: Consultancy; Catalyst Bioscience: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy; uniQure: Consultancy; BioMarin: Consultancy; Pfizer: Consultancy; Spark Therapeutics: Consultancy. Becka:Bayer: Employment. Detering:Bayer: Employment. Vanevski:Bayer: Employment. Lissitchkov:Octapharma: Equity Ownership, Research Funding; Bayer: Consultancy, Equity Ownership, Honoraria, Other: Principal investigator for clinical trials, Research Funding; Sobi: Consultancy, Equity Ownership, Honoraria; Sanofi: Equity Ownership, Research Funding; Roche: Consultancy, Equity Ownership, Honoraria, Speakers Bureau; Shire: Consultancy, Equity Ownership, Honoraria, Speakers Bureau. OffLabel Disclosure: Gene therapy for haemophilia treatment.

Aims This study investigated relevant pharmacodynamic and pharmacokinetic parameters during the transition from warfarin to rivaroxaban in healthy male subjects. Methods Ninety-six healthy men were randomized into the following three groups: warfarin [international normalized ratio (INR) 2.0–3.0] transitioned to rivaroxaban 20 mg once daily (od; group A); warfarin (INR 2.0–3.0) followed by placebo od (group B); and rivaroxaban alone 20 mg od (group C) for 4 days. Anti-factor Xa activity, inhibition of factor Xa activity, prothrombin time (PT), activated partial thromboplastin time, HepTest, prothrombinase-induced clotting time, factor VIIa activity, factor IIa activity, endogenous thrombin potential and pharmacokinetics were measured. Results An additive effect was observed on the PT and PT/INR during the initial transition period. The mean maximal prolongation of PT was 4.39-fold [coefficient of variation (CV) 18.03%; range 3.39–6.50] of the baseline value in group A, compared with 1.88-fold (CV 10.35%; range 1.53–2.21) in group B and 1.57-fold (CV 9.98%; range 1.37–2.09) in group C. Rivaroxaban had minimal influence on the PT/INR at trough levels. Inhibition of factor Xa activity, activated partial thromboplastin time and endogenous thrombin potential were also enhanced, but to a lesser extent. In contrast, the effects of rivaroxaban on anti-factor Xa activity, HepTest and prothrombinase-induced clotting time were not affected by pretreatment with warfarin. Conclusions Changes in pharmacodynamics during the transition from warfarin to rivaroxaban vary depending on the test used. A supra-additive effect on PT/INR is expected during the initial period of transition, but pretreatment with warfarin does not influence the effect of rivaroxaban on anti-factor Xa activity.

Rivaroxaban is an oral, direct Factor Xa inhibitor that targets free and clot-bound Factor Xa and Factor Xa in the prothrombinase complex. It is absorbed rapidly, with maximum plasma concentrations being reached 2-4 h after tablet intake. Oral bioavailability is high (80-100 %) for the 10 mg tablet irrespective of food intake and for the 15 mg and 20 mg tablets when taken with food. Variability in the pharmacokinetic parameters is moderate (coefficient of variation 30-40 %). The pharmacokinetic profile of rivaroxaban is consistent in healthy subjects and across a broad range of different patient populations studied. Elimination of rivaroxaban from plasma occurs with a terminal half-life of 5-9 h in healthy young subjects and 11-13 h in elderly subjects. Rivaroxaban produces a pharmacodynamic effect that is closely correlated with its plasma concentration. The pharmacokinetic and pharmacodynamic relationship for inhibition of Factor Xa activity can be described by an E max model, and prothrombin time prolongation by a linear model. Rivaroxaban does not inhibit cytochrome P450 enzymes or known drug transporter systems and, because rivaroxaban has multiple elimination pathways, it has no clinically relevant interactions with most commonly prescribed medications. Rivaroxaban has been approved for clinical use in several thromboembolic disorders.

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).

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.

A randomized, single-blind, placebo-controlled, parallel-group study was conducted to assess the effect of age and gender on the pharmacokinetics and pharmacodynamics of rivaroxaban – an oral, direct Factor Xa inhibitor. Subjects (n = 34) were enrolled into four groups: young males or females (aged 18–45 years) and elderly males or females (aged >75 years), and received a single dose of 10 mg rivaroxaban. Pharmacokinetic and pharmacodynamic parameters were determined. Gender had no significant influence on the pharmacokinetics and pharmacodynamics of rivaroxaban. The area under the concentration–time curve (AUC) of rivaroxaban was 41% higher in elderly compared with young subjects; corresponding AUC values for the inhibition of Factor Xa activity and prolongation of prothrombin time were also higher. These changes were the result of reduced rivaroxaban clearance in elderly subjects, mainly owing to decreased renal function. The influence of age was not considered clinically relevant. The maximum plasma concentration was not increased in elderly subjects, and pharmacodynamic parameters returned close to baseline within 24 hours. The results indicate that age alone and gender did not have a clinically relevant effect on the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy subjects after a 10 mg dose.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Prior to the commencement of this study, it was already known that rivaroxaban is partially cleared via the kidneys and an influence of renal insufficiency on rivaroxaban pharmacokinetics and exposure was anticipated. WHAT THIS STUDY ADDS • As many patients in the target indications of rivaroxaban will be elderly, a precise quantitative knowledge of the influence of renal function on rivaroxaban pharmacokinetics and exposure is mandatory for adequate labelling recommendations (in the context of benefit/risk provided by phase III studies) to guide therapy. This study provided detailed insight on both rivaroxaban pharmacokinetics and pharmacodynamic behaviour in renal impairment including severely renally impaired subjects. AIM This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10 mg single dose), an oral, direct Factor Xa inhibitor. METHODS Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80 ml min−1), mild (50–79 ml min−1), moderate (30–49 ml min−1) and severe impairment (

Groups of five male and five female Wistar rats were treated by gavage with 0, 1, 10, and 100 mg/kg body weight (b.w.) flutamide (FLU) or 0.01, 0.05, and 0.2 mg/kg b.w. of ethinylestradiol (EE2) for at least 28 days according to an enhanced Organization for Economic Cooperation and Development (OECD) test guideline (TG) 407 to investigate which of the current and/or additional parameters would detect effects on the endocrine system and to provide data on intralaboratory variability. Two identical studies were performed in parallel on each compound. Common enhancements were determination of thyroid hormones (T3, T4) and thyroid stimulating hormone (TSH), of the stage of the estric cycle to ensure necropsy of females in diestrus, of the number and morphology of epididymal sperm, and of additional organ weights (e.g., male accessory sex organs, MASO) and histopathology of additional organs (e.g., pituitary, vagina). Endocrine-mediated findings consistently observed in these studies were decreased relative weights of MASO at 100 mg/kg FLU and at 0.2 mg/kg EE2, histological changes in pituitary and testes at > or = 10 mg/kg and in MASO, epididymis and adrenals at 100 mg/kg in FLU-treated males, histological changes in the mammary gland at > or = 0.05 mg/kg and in testes, MASO and adrenals at 0.2 mg/kg in EE2-treated males, estrogenization of uterus and vagina (despite necropsy in diestrus) at > or = 0.01 mg/kg EE2, and changes in the ovary at 0.2 mg/kg EE2. Spermatology was insensitive (EE2) or revealed changes only at the maximum tolerated dose (MTD). Determination of T3, T4, and TSH did not contribute to the detection of the endocrine effects (FLU) or provided equivocal results. Doubling the group size to 10 animals by combining the studies run in parallel did not increase the sensitivity of detection of endocrine-mediated effects above the level obtained by histopathological examination of groups of five animals. Only some of the proposed enhancements evaluated were helpful in detecting the endocrine-mediated effects of FLU and EE2. Evaluation of studies according to an enhanced TG 407 on 10 compounds with different endocrine activities will identify the most appropriate enhancements.

The statistical analysis of dynamic processes is a useful tool to learn how environmental and ecological systems work and how they respond to disturbances. In the context of human risk assessment of potentially harmful chemicals, many complex dynamic processes in terms of kinetics have to be taken into account. Thorough research of direct influence of chemicals to humans depends on investigations with animalsin vivo andin vitro. However, when animals serve as models of human systems, one critical step is the extrapolation from the risk observed in the experimental animals to the risk associated with the human organism. To extrapolate the observed risk in this case, the detailed knowledge of the relevant kinetic processes as well as their differences between species is fundamental. On the other hand experimental tools for these processes are quite restrictive. Based on simple experimental designs a statistical method is proposed for characterizing such kinetic processes using the well-known compartmental analysis tool and non-linear regression. The methodology is then exemplified by non-invasive toxicokinetic inhalation experiments with rats.

Objective: To investigate potential interactions between rivaroxaban, an oral direct Factor Xa inhibitor approved for the management of thromboembolic disorders, and digoxin or atorvastatin. Methods: Two randomized, phase 1 clinical trials were undertaken in healthy men to assess pharmacokinetic and pharmacodynamic interactions between rivaroxaban and digoxin or atorvastatin, and the safety of these drug combinations. Results: Steady-state rivaroxaban did not affect the pharmacokinetic profile of steady-state digoxin ( n = 17). Digoxin did not significantly influence the pharmacokinetic profile of single-dose rivaroxaban and had minimal effects on rivaroxaban-induced inhibition of Factor Xa activity and prolongation of clotting time. Similarly, steady-state atorvastatin did not affect the pharmacokinetic profile or the pharmacodynamics of rivaroxaban and vice versa ( n = 19). All drugs (alone or in combination) were well tolerated. Conclusions: There were no clinically relevant pharmacokinetic or pharmaco - dynamic interactions between rivaroxaban and digoxin, or between rivaroxaban and atorvastatin, suggesting that rivaroxaban can be coadministered with either drug. This study also confirmed that rivaroxaban does not interact with substrates for permeability (P)-glycoprotein alone (digoxin) or P-glycoprotein and cytochrome P450(CYP)3A4 (atorvastatin).

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.

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.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).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.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.

This study evaluated the effects of impaired renal function on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban (10mg single dose), an oral, direct Factor Xa inhibitor.Subjects (n= 32) were stratified based on measured creatinine clearance: healthy controls (≥80ml min(-1) ), mild (50-79mlmin(-1) ), moderate (30-49mlmin(-1) ) and severe impairment (30mlmin(-1) ).Renal clearance of rivaroxaban decreased with increasing renal impairment. Thus, plasma concentrations increased and area under the plasma concentration-time curve (AUC) LS-mean values were 1.44-fold (90% confidence interval [CI] 1.1, 1.9; mild), 1.52-fold (90% CI 1.2, 2.0; moderate) and 1.64-fold (90% CI 1.2, 2.2; severe impairment) higher than in healthy controls. Corresponding values for the LS-mean of the AUC for prolongation of prothrombin time were 1.33-fold (90% CI 0.92, 1.92; mild), 2.16-fold (90% CI 1.51, 3.10 moderate) and 2.44-fold (90% CI 1.70, 3.49 severe) higher than in healthy subjects, respectively. Likewise, the LS-mean of the AUC for Factor Xa inhibition in subjects with mild renal impairment was 1.50-fold (90% CI 1.07, 2.10) higher than in healthy subjects. In subjects with moderate and severe renal impairment, the increase was 1.86-fold (90% CI 1.34, 2.59) and 2.0-fold (90% CI 1.44, 2.78) higher than in healthy subjects, respectively.Rivaroxaban clearance is decreased with increasing renal impairment, leading to increased plasma exposure and pharmacodynamic effects, as expected for a partially renally excreted drug. However, the influence of renal function on rivaroxaban clearance was moderate, even in subjects with severe renal impairment.

What is already known about this subject • Rivaroxaban is a novel anticoagulant with predictable, dose-proportional pharmacokinetics and pharmacodynamics in healthy subjects. • It is in clinical development for the prevention of thromboembolic disorders in patients undergoing major orthopaedic surgery. • Nonsteroidal anti-inflammatory drugs (NSAIDs), such as naproxen, are widely used for pain relief and treatment of inflammation, particularly in patients who have undergone orthopaedic surgery. As it is likely that patients receiving rivaroxaban after orthopaedic surgery will also receive NSAIDs, this study was performed to determine whether there was any mechanistic interaction between rivaroxaban and naproxen. What this study adds • This study demonstrated that there was no mechanistic interaction between rivaroxaban and naproxen in healthy subjects. • This finding was used to design large-scale clinical trials of rivaroxaban, in which patients were also allowed to use NSAIDs. • These ongoing trials will provide definitive data regarding the interaction between rivaroxaban and NSAIDs. Aims Rivaroxaban (BAY 59-7939) is in advanced clinical development for the prevention and treatment of thromboembolic disorders. Frequent co-medications in the patient populations likely to receive rivaroxaban include NSAIDs. This randomized, two-way crossover study, with a naproxen run-in period, was performed to determine whether naproxen influences the tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban. Methods Eleven healthy, young males received naproxen 500 mg on two consecutive days, a single dose of rivaroxaban 15 mg, or both. Results Treatments were well tolerated: adverse events (eight in total), reported by three subjects, were mild and not drug related. Rivaroxaban inhibited Factor Xa activity by 35% and prolonged prothrombin time [by 1.4 times baseline (tb)], activated partial thromboplastin time (1.3 tb) and the HepTest (1.9 tb). Naproxen had no influence on these measures and the combination of rivaroxaban and naproxen did not affect platelet aggregation. Rivaroxaban and naproxen given together significantly increased bleeding time compared with rivaroxaban alone (P = 0.017). However, this difference was small compared with the effect of naproxen given alone, except in one subject. Least squares-means ratios for the AUC and Cmax of rivaroxaban after administration alone and with naproxen were 1.125 [90% confidence interval (CI) 0.995, 1.271] and 1.095 (90% CI 0.905, 1.325), respectively. Conclusions There appeared to be no clinically relevant interaction between rivaroxaban and naproxen in healthy subjects, although some individuals may be more sensitive to the combination. Large-scale Phase III clinical studies will be required to confirm whether there is an increased risk of bleeding during treatment with rivaroxaban and concomitant NSAIDs.

Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis.In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples.The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02; P.0001; 95% confidence interval, .758-.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists' agreement over histologic scores ranged from very good to moderate (kappa = .97-.46).Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.

Rivaroxaban (BAY 59-7939) is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. It has predictable pharmacokinetics and pharmacodynamics in healthy subjects. Approximately 30% of rivaroxaban is excreted unchanged in the urine; therefore, renal excretion is an important route of elimination. This multicenter study was performed to evaluate the effect of renal impairment on the tolerability, pharmacokinetics, and pharmacodynamics of a single oral 10 mg dose of rivaroxaban. Subjects (N=32) were allocated to one of four groups (matched by age and gender), based on calculated creatinine clearance (CrCL): ≥80 mL/min (control); 50–79 mL/min (mild impairment); 30–49 mL/min (moderate impairment); and

Anticoagulants, such as warfarin, are indicated for a variety of medical conditions, some of which are strongly age dependent. In younger people, the prevalence of many cardiovascular diseases is typically higher in males; however, with increasing age, this difference often resolves. Rivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. This randomized, single-blind study was performed to investigate the influences of age and gender on the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of rivaroxaban in healthy subjects. Four subject groups (young males or females, aged 18–45 years, and elderly males or females, aged >75 years) received a single dose of rivaroxaban 10 mg or placebo (N=34). Gender had no effect on the area under the plasma concentration-time curve (AUC), or maximum plasma concentration (Cmax) of rivaroxaban (Table); however, elderly subjects had higher AUC values than young subjects (least-squares mean ratio [LS-mean] 1.41, 90% confidence interval [CI] 1.20–1.66). The Cmax of rivaroxaban was unaffected by age (LS-mean 1.08, 90% CI 0.96–1.25). Total and renal clearance of rivaroxaban correlated positively with creatinine clearance (CrCL), and inversely with age. The patterns of inhibition of FXa activity by rivaroxaban for all groups were mirrored by those of prolongation of prothrombin time (PT); the maximum effect (Emax) of both consistently occurred 2–4 hours after administration and was unaffected by age or gender. In parallel with the PK results, the AUC of the PD effect, from administration of rivaroxaban to the final time point (AUC0-tn), was increased in elderly subjects (inhibition of FXa activity, LS-mean 1.58, 90% Cl 1.32–1.89; prolongation of PT, LS-mean 1.46, 90% Cl 1.29–1.66); however, all values returned to within 10% of baseline 24 hours after administration of rivaroxaban. The AUC0-tn values correlated inversely with CrCL. Rivaroxaban was well tolerated by all groups; the incidence and intensity of adverse events was similar to placebo. In conclusion, these results demonstrate that the observed effect of age on the PK and PD of this rivaroxaban dose - increased AUC in elderly subjects - was largely due to reduced renal function. Gender had virtually no effect on the PK and PD of rivaroxaban, and neither age nor gender affected tolerability. These findings suggest that rivaroxaban, at similar doses, may not require dose adjustment in elderly patients, or for gender. Phase II studies of rivaroxaban for the prevention of venous thromboembolism also suggested that dose adjustment may not be required for age or gender in this indication. However, this will require confirmation in large-scale phase III studies. | | Young males | Young females | Elderly males | Elderly females | |:------------------------------------------------------------------ | ------------ | ------------- | ------------- | --------------- | | Values are geometric means/geometric coefficients of variation (%) | | AUC (μg·h/L) | 1477/29.97 | 1210/12.69 | 1839/28.24 | 1941/16.15 | | Cmax (μg/L) | 227.57/18.25 | 209.73/23.95 | 228.80/23.79 | 245.01/18.23 | | Inhibition of FXa | | | | | | Emax (%) | 50.86/16.84 | 53.99/12.44 | 56.30/6.39 | 60.16/9.01 | | AUC0-tn (%/h) | 432.76/38.75 | 343.14/24.61 | 613.94/11.09 | 596.48/23.20 | | Prolongation of PT | | | | | | Emax (x-fold) | 1.62/9.06 | 1.69/8.49 | 1.66/5.67 | 1.75/4.63 | | AUC0-tn (x-fold/h) | 22.69/28.09 | 15.98/10.41 | 29.77/3.15 | 26.06/17.52 | PK and PD parameters in subjects receiving rivaroxaban 10 mg (n=6 in each group)

Currently, agents used for the prevention of venous thromboembolism, such as low molecular weight heparins and pentasaccharides, require dose adjustments for patients in extreme weight categories. BAY 59-7939 is a novel, oral, direct Factor Xa (FXa) inhibitor currently undergoing clinical development for the prevention and treatment of thromboembolic disorders. In this single-center, randomized, single-blind, placebo-controlled, parallel-group study, the influence of extremely low and high body weight on the safety, tolerability, pharmacodynamics and pharmacokinetics of a single 10 mg dose of BAY 59-7939 administered with food was investigated. In total, 48 healthy male and female subjects aged 20–54 years and in three different weight groups (≤ 50, 70–80, and >120 kg) were evaluated; 12 received placebo and 36 received BAY 59-7939. The 70–80 kg and >120 kg groups were gender-balanced (six men and six women in each group); the ≤ 50 kg group comprised of 12 women. Overall, BAY 59-7939 was well tolerated. No serious adverse events were reported; all events were of mild to moderate intensity and resolved 7 days after drug administration. The occurrence of adverse events was similar among the weight groups. No adverse events were reported in the placebo group. FXa was inhibited by BAY 59-7939 in all three weight groups, with a maximum inhibition (Emax) of 46.8%, 45.8%, and 41.7% in the ≤ 50, 70–80, and >120 kg groups, respectively; maximum inhibition was observed about 2–3 hours after BAY 59-7939 administration in all three weight groups. AUC for inhibition of Factor Xa activity was comparable for all volunteer groups regardless of the body weight. BAY 59-7939 prolonged prothrombin time (PT), which was less pronounced in the higher weight groups: 1.7 times baseline (tb), 1.6 tb, and 1.5 tb in subjects ≤ 50, 70–80, and >120 kg, respectively. The pharmacodynamic parameters have returned to baseline within 24 hours in all weight groups. Placebo treatment had no effect on PT. The clotting tests activated partial thromboplastin time and HepTest were also distinctly prolonged after drug administration in all weight groups; the prolongation was slightly more pronounced in subjects in the ≤ 50 kg group than in the other weight groups. The bioavailability of BAY 59-7939 as a 10 mg single dose, in terms of AUC of plasma concentrations, was similar in all three weight groups (P=0.205). However, peak plasma concentrations (Cmax) were 24% higher in subjects with ≤ 50 kg body weight compared with normal-weight subjects. For subjects >120 kg, Cmax was similar to normal-weight subjects. No pharmacokinetic differences between men and women were detected in the normal-weight and >120 kg groups. In conclusion, these data demonstrate that only small influences of body weight on pharmacodynamic or pharmacokinetic parameters are observed which require no dose adjustment of BAY 59-7936 in subjects with extreme body weight.

IntroductionCinaciguat (BAY 58-2667) is an nitric oxide (NO)-inde-pendent and heme-independent soluble guanylatecyclase (sGC) activator. Cinaciguat preferentially acti-vates sGC in its oxidized or heme-free state, when theenzyme is insensitive to its endogenous ligand NO andexogenous nitrovasodilators [1].Endothelium-derived NO is one of the mechanisms bywhich platelet aggregation and thrombus formation isprevented by the intact blood vessel wall. Pharmacologi-cal stimulation of sGC in platelets correlates with inhibi-tion of aggregation, platelet cGMP increase, prolongationof bleeding time and antithrombotic effects in vitro [2].This protective mechanism may be impaired in vasculardisease and impaired NO availability. Thus, sGC activa-tors may have antithrombotic effects similar to endogen-ous NO. Indeed, cinaciguat potently inhibited plateletaggregation induced by the thromboxane mimic U46619and collagen and prolonged rat-tail bleeding time up to2-fold [3]. Thus, in vitro data suggested that coadminis-tration of cinaciguat and aspirin may increase the antipla-telet effects of aspirin and could result in bleeding.MethodsThis non-randomized, open-label trial was conductedfrom September to November 2001 in a single center inGermany. It was carried out in accordance with theDeclaration of Helsinki and adhered to the InternationalConference of Harmonization good clinical practiceguidelines and the German drug law (AMG). The studyprotocol was approved by the Ethics Committee of theNorth-Rhine Medical Council, Duesseldorf, Germany.The study consisted of a 9-day treatment phase with100 mg oral acetylsalicylicacid (aspirin) once dailyadministered in the morning in the fasting state and,after the last dose of aspirin, four sequential oral dosesof 1.5 mg cinaciguat administered in the fasting state at1-hour intervals. The first dose of cinaciguat was admi-nistered together with the last dose of aspirin. This cina-ciguat dosing schedule was used to mimic a prolongedplasma concentration over time profile.Results12 healthy men (mean age, 32.4 years, range, 23 - 42years) were enrolled and completed the study accordingto protocol.Low-dose aspirin treatment in healthy subjectsresulted in the expected inhibition of platelet aggrega-tion. 4 oral doses of 1.5 mg cinaciguat administered at1-hour intervals did not significantly affect plateletaggregation induced by collagen and the thromboxaneA2 mimetic U 46619 or bleeding time. These results arein line with the findings of a single dose escalationstudy.Plasma pharmacokinetics of cinaciguat following 4oral doses of 1.5 mg cinaciguat administered at 1-hourintervals showed pronounced inter-individual variability.There was no major pharmacokinetic interactiondetected between aspirin and cinaciguat, compared withthe data of a previous study, which applied the samedosing regimen.ConclusionCoadministration of cinaciguat and aspirin did notreveal any pharmacodynamic interaction with respect of