Kenneth Todd Moore

Pharmacokinetics, Pharmacodynamics, and Safety of Single-Dose Rivaroxaban in Chronic Hemodialysis.

Background: This study aimed to characterize the single-dose pharmacokinetic (PK) and pharmacodynamic (PD) profile of rivaroxaban 15 mg administered before and after dialysis in subjects with end-stage renal disease (ESRD), and to compare this profile in subjects with ESRD to that in healthy control subjects (creatinine clearance ≥80 ml/min). Methods: This was an open-label, single-dose, single-center, parallel-group study of rivaroxaban in ESRD subjects who had been clinically stable on maintenance hemodialysis for ≥3 months. In 8 subjects with ESRD, a 15-mg dose of rivaroxaban was administered 2 ± 0.5 h before a hemodialysis session and repeated 7-14 days later at 3 h after a 4-h hemodialysis session. Eight healthy control subjects, matched for age, sex, and body mass index, received one 15-mg rivaroxaban dose. Results: Compared to healthy subjects, area under the rivaroxaban plasma concentration versus time curve (AUC) increased by 56% following post-dialysis administration. Assuming similar bioavailability between groups, this reflects an approximate 35% decrease in overall drug clearance in ESRD subjects. Pre-dialysis dosing resulted in only 5% lowering of AUC versus post-dialysis dosing, confirming the minimal impact of dialysis on the PK of rivaroxaban. PD effects, as assessed by change in prothrombin time, percent factor Xa inhibition, and anti-Xa activity, were generally concordant with observed changes in plasma PK. Conclusions: Changes in PK and PD parameters in chronic dialysis patients were generally comparable to changes observed previously in patients with moderate-to-severe renal impairment who were not undergoing dialysis, and support use of a 15-mg dose in this patient population.

Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban.

Abstract Many patients with acute coronary syndrome receive chronic dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) for secondary event prophylaxis, and new oral anticoagulants are being investigated as adjunctive therapy in this indication. Gastrointestinal side effects such as bleeding are commonly associated with antiplatelet use; accordingly, many patients receive proton pump inhibitors (PPIs) to mitigate this. PPIs can reduce the antiplatelet activity of clopidogrel through cytochrome P450 2C19 inhibition, and pantoprazole reduces the bioavailability of dabigatran, a direct thrombin inhibitor that acts via cytochrome P450 2C19-independent mechanisms. These observations support the investigation of potential pharmacokinetic and pharmacodynamic interactions between PPIs and anticoagulants. We evaluated the influence of administering once-daily omeprazole 40 mg for 5 days on the pharmacokinetics and pharmacodynamics of a single 20-mg dose of the oral direct factor Xa inhibitor, rivaroxaban, in a randomized, open-label, 2-way, crossover, drug–drug interaction study in healthy subjects. No clinically meaningful interactions were observed; geometric mean ratios were 101%, 101%, and 93.5% for rivaroxaban area under the plasma concentration–time curve from time 0 to the time of the last quantifiable concentration (AUClast), or until infinity (AUC∞), and maximum plasma concentration (Cmax), respectively. Prothrombin time increased similarly in both treatment groups, with maximal values observed approximately 4 hours post rivaroxaban administration. A single 20-mg rivaroxaban dose appears well tolerated when administered alone or after 5 days of once-daily omeprazole 40 mg administration.

Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Population pharmacokinetics and pharmacodynamics of rivaroxaban have been characterized in healthy subjects and in patients with total venous thromboembolism, deep vein thrombosis or atrial fibrillation. WHAT THIS STUDY ADDS • This article is the first description of the population pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in patients with acute coronary syndrome (ACS). It is the largest population pharmacokinetic and pharmacodynamic study on rivaroxaban conducted to date (n= 2290). The PK and PK-PD relationship of rivaroxaban in patients with ACS were similar to those in other patient populations. In addition, model-based simulations showed that the influence of renal function and age on the exposure to rivaroxaban in the ACS population were similar to the findings from Phase 1 special population studies. These findings suggest that rivaroxaban has highly predictable PK-PD and may provide a consistent anticoagulant effect across the studied patient populations, which allows an accurate prediction of the dose to control anticoagulation optimally. AIMS The aim of this analysis was to use a population approach to facilitate the understanding of the pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndrome (ACS) and to evaluate the influence of patient covariates on the exposure of rivaroxaban in patients with ACS. METHODS A population pharmacokinetic model was developed using pharmacokinetic samples from 2290 patients in Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 46. The relationship between pharmacokinetics and the primary pharmacodynamic end point, prothrombin time, was evaluated. RESULTS The pharmacokinetics of rivaroxaban in patients with ACS was adequately described by an oral one-compartment model. The estimated absorption rate, apparent clearance and volume of distribution were 1.24 h(-1) (interindividual variability, 139%), 6.48 l h(-1) (31%) and 57.9 l (10%), respectively. Simulations indicate that the influences of renal function, age and bodyweight on exposure in ACS patients are consistent with the findings in previous Phase 1 studies. Rivaroxaban plasma concentrations exhibit a close-to-linear relationship with prothrombin time in the ACS population, with little interindividual variability. The estimated pharmacokinetic and pharmacodynamic parameters for the ACS patients were comparable to those for venous thromboembolism prevention, deep vein thrombosis and atrial fibrillation patients. CONCLUSIONS The similarity in pharmacokinetics/pharmacodynamics of rivaroxaban among different patient populations and the low interindividual variability in the exposure-prothrombin time relationship indicate that the anticoagulant effect of rivaroxaban is highly predictable and consistent across all the patient populations studied.

An open-label study to estimate the effect of steady-state erythromycin on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban in subjects with renal impairment and normal renal function

Two previously conducted rivaroxaban studies showed that, separately, renal impairment (RI) and concomitant administration of erythromycin (P‐glycoprotein and moderate cytochrome P450 3A4 [CYP3A4] inhibitor) can result in increases in rivaroxaban exposure. However, these studies did not assess the potential for combined drug–drug–disease interactions, which—in theory—could lead to additive or synergistic increases in exposure. This study investigated rivaroxaban pharmacokinetics and pharmacodynamics when co‐administered with steady‐state (SS) erythromycin in subjects with either mild or moderate RI. Similar to previous studies, rivaroxaban administered alone in RI subjects, or when co‐administered with SS erythromycin in normal renal function (NRF) subjects, increased rivaroxaban exposure. When combined, the co‐administration of rivaroxaban 10 mg with SS erythromycin in subjects with mild or moderate RI produced mean increases in rivaroxaban AUC∞ and Cmax of approximately 76% and 56%, and 99% and 64%, respectively, relative to NRF subjects, with PD changes displaying a similar trend. No serious adverse events occurred and no persistent adverse events were reported at the end of study. Although these increases were slightly more than additive, rivaroxaban should not be used in patients with RI receiving concomitant combined P‐glycoprotein and moderate CYP3A4 inhibitors, unless the potential benefit justifies the potential risk.

Rivaroxaban crushed tablet suspension characteristics and relative bioavailability in healthy adults when administered orally or via nasogastric tube

Because some patients have difficulty swallowing a whole tablet, we investigated the relative bioavailability of a crushed 20 mg rivaroxaban tablet and of 2 alternative crushed tablet dosing strategies.

Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis‐mediated conditions

The development of rivaroxaban (XARELTO®) is an important new medical advance in the field of oral anticoagulation. Thrombosis‐mediated conditions constitute a major burden for patients, healthcare systems, and society. For more than 60 years, the prevention and treatment of these conditions have been dominated by oral vitamin K antagonists (such as warfarin) and the injectable heparins. Thrombosis can lead to several conditions, including deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke, and/or death. Prevention and treatment of thrombosis with an effective, convenient‐to‐use oral anticoagulant with a favorable safety profile is critical, especially in an aging society in which the risk of thrombosis, and the potential for bleeding complications, is increasing. Rivaroxaban acts to prevent and treat thrombosis by potently inhibiting coagulation Factor Xa in the blood. Factor Xa converts prothrombin to thrombin, which initiates the formation of blood clots by converting fibrinogen to clot‐forming fibrin and leads to platelet activation. After a large and novel clinical development program in over 75,000 patients to date, rivaroxaban has received approval for multiple indications in the United States, European Union, and other countries worldwide to prevent and treat several thrombosis‐mediated conditions. This review will highlight some of the unique aspects of the rivaroxaban development program.

Switching from rivaroxaban to warfarin: an open label pharmacodynamic study in healthy subjects

Aims The primary objective was to explore the pharmacodynamic changes during transition from rivaroxaban to warfarin in healthy subjects. Safety, tolerability and pharmacokinetics were assessed as secondary objectives. Methods An open label, non-randomized, sequential two period study. In treatment period 1 (TP1), subjects received rivaroxaban 20 mg once daily (5 days), followed by co-administration with a warfarin loading dose regimen of 5 or 10 mg (for the 10 mg regimen, the dose could be uptitrated to attain target international normalized ratio [INR] ≥2.0) once daily (2–4 days). When trough INR values ≥2.0 were attained, rivaroxaban was discontinued and warfarin treatment continued as monotherapy (INR 2.0–3.0). During treatment period 2, subjects received the same warfarin regimen as in TP1, but without rivaroxaban. Results During co-administration, maximum INR and prothrombin time (PT) values were higher than with rivaroxaban or warfarin monotherapy. The mean maximum effect (Emax) for INR after co-administration was 2.79–4.15 (mean PT Emax 41.0–62.7 s), compared with 1.41–1.74 (mean PT Emax 20.1–25.2 s) for warfarin alone. However, rivaroxaban had the smallest effect on INR at trough rivaroxaban concentrations. Neither rivaroxaban nor warfarin significantly affected maximum plasma concentrations of the other drug. Conclusions The combined pharmacodynamic effects during co-administration of rivaroxaban and warfarin were greater than additive, but the pharmacokinetics of both drugs were unaffected. Co-administration was well tolerated. When transitioning from rivaroxaban to warfarin, INR monitoring during co-administration should be performed at the trough rivaroxaban concentration to minimize the effect of rivaroxaban on INR.

Influences of Obesity and Bariatric Surgery on the Clinical and Pharmacologic Profile of Rivaroxaban

The health implications of obesity are myriad and multifaceted. Physiologic changes associated with obesity can affect the absorption, distribution, metabolism, and excretion of administered drugs, thereby altering their pharmacologic profiles. In 2016, the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis published recommendations about the use of direct oral anticoagulants (DOACs) in obese patients. This guidance provides uniform recommendations for all DOACs, yet data suggest that individual agents may be affected to different degrees by obesity. Moreover, there are no recommendations currently available to guide DOAC use in bariatric surgery patients, in whom anatomic and physiologic changes to the digestive system can influence drug pharmacokinetics. Our review of the available literature indicates that the clinical profile of the DOAC rivaroxaban is not affected by high weight or bariatric surgery; hence, it does not appear that rivaroxaban dosing needs to be altered in these patient populations.

Clarification-safety and efficacy of apixaban versus warfarin in patients with end-stage renal disease: Meta-analysis

Dear Editor, I would like to bring to your attention an error observed in the above-mentioned manuscript. The manuscript states that “At the present, apixaban is the only non-vitamin K oral anticoagulant (NOAC) approved by the FDA for use with patients with creatinine clearance <15 mL/min or end-stage renal disease (ESRD).” This is incorrect; both the apixaban and rivaroxaban labels have similar recommendations for patients diagnosedwith ESRD and atrial fibrillation. These recommendations can be found in Section 8.6 of the respective labels. Regarding the rivaroxaban and apixaban labels, both sponsors performed a similarly designed trial which consisted of an open-label, parallel groupdesign: they enrolled16adult subjects (eightwithESRDand eight with normal renal function); administered a single dose of medication (apixaban 5 mg/rivaroxaban 15 mg), once for those with normal renal function and twice for those with ESRD (once prior to dialysis and once after dialysis, separated by a washout period); collected serial pharmacokinetic and pharmacodynamic blood samples prior to dose and up to 72 hours postdose; and each trial was conducted at a single research center in the United States. The only significant deviation in design between the two studies was the use of saline or unfractionated heparin (UFH) during dialysis to keep the lines patent. Apixaban utilized saline, while rivaroxaban utilized a low dose of UFH.1,2 While direct comparisons cannot be made as they were two separate studies, the pattern of results was similar for both compounds. That is, the overall increase in systemic exposure postdialysis (as measured by the area under the curve [AUC]) was 36% for apixaban and 56% for rivaroxaban, which is representative of the decrease in overall clearance expected with complete loss of kidney function for these compounds, respectively.1,2 We also see a similar pattern of increasing exposure when assessing the progressive decline of renal function. For example, apixaban displays an approximate 16%, 29%, 38%, and 36% increase in AUC for those subjects with mild, moderate, and

American Geriatrics Society Beers Criteria and Anticoagulant Use in Older Adults With Renal Impairment

mgof dry liver isw7 g ofmobilized excess iron (Figure 1, dashed line), whereas 21 mmol/100 mg dry liver isw14 g (Figure 1, solid lines). If we solve using the regression equation of Brissot et al. (LIC 1⁄4 (1.3 mobilized excess iron) þ 3.5), then the TBI is 7.3 g and 13.6 g, respectively, for these 2 examples. Based on Rottembourg’s expected hemodialysis annual blood losses, (1.68 g/yr), patients with severe iron overload by MRI-LIC would take at least 8.0 years to normalize their LIC, and yet Rostoker’s group reports that they did this in 10 to 12 months. Additionally, Figure 2 of Brissot et al. demonstrates that semiquantitative histologic estimates of LIC, as Rostoker used in another publication, frequently overestimate the actual LIC. At least one-half of the grade 2 LIC estimates had normal actual LIC, whereas w15% of grade 3 LIC estimates had normal LIC, and many others should have been categorized as grade 2. In summary, these data indicate that MRI-LIC measurement in dialysis patients overestimates TBI by a factor of 10 when applying Brissot’s equation, whereas I conservatively estimated that they were off by a factor of 3 to 6. Brissot also demonstrates that histologic assessments of LIC are inferior to actual determinations. I could not have made my points any better.