Rivaroxaban Crushed Tablet Suspension Characteristics and Relative Bioavailability in Healthy Adults When Administered Orally or Via Nasogastric Tube

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1 Original Article Rivaroxaban Crushed Tablet Suspension Characteristics and Relative Bioavailability in Healthy Adults When Administered Orally or Via Nasogastric Tube Clinical Pharmacology in Drug Development 3(4) , The American College of Clinical Pharmacology DOI: /cpdd.123 Kenneth T. Moore 1, Mark A. Krook 2, Seema Vaidyanathan 1, Troy C. Sarich 2, C. V. Damaraju 2, and Larry E. Fields 3 Purpose: 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. Methods: Stability and nasogastric (NG) tube adsorption characteristics of a crushed rivaroxaban tablet were assessed. Then, in 55 healthy adults, relative bioavailability of rivaroxaban administered orally as a whole tablet (Reference [Whole Oral]), crushed tablet in applesauce suspension (Crushed Oral), or crushed tablet in water suspension via NG tube (Crushed NG) were determined. Results: There were no significant changes in mean percent of non degraded rivaroxaban recovered over 4 hours from crushed tablet suspensions (>98.4% recovery across all suspensions and time points) or after NG tube exposure (recovery: 99.1% for silicone and 98.9% for polyvinyl chloride NG tubes). Relative bioavailability was similar between Crushed Oral and Reference dosing (C max and AUC 1 were within the % bioequivalence limits). Relative bioavailability was also similar between the Crushed NG and Reference dosing (AUC 1 was within bioequivalence limits; C max [90% CI range: %] was only slightly below the 80% lower bioequivalence limit). Conclusions: A crushed rivaroxaban tablet was stable and when administered orally or via NG tube, displayed similar relative bioavailability compared to a whole tablet administered orally. Keywords rivaroxaban, factor Xa inhibitor, nasogastric tube, bioavailability, pharmacokinetics Rivaroxaban is a novel oral anticoagulant that selectively inhibits factor Xa (FXa) at the beginning of the final common pathway of the coagulation cascade; thus, blocking the downstream burst of thrombin generation. 1 4 Rivaroxaban is readily absorbed after oral tablet administration, with maximum plasma concentrations (C max ) occurring approximately 2 4 hours after dosing. 5,6 The 20 mg tablet displays an absolute bioavailability of approximately 66% in a fasted state, increasing by approximately 39% when administered with food. 7 A similar absorption profile and food effect may be expected for the 15 mg tablet. Therefore, both dose strengths should be administered with food. Both doses are approved for DVT or PE treatment, reducing the risk of DVT and PE recurrence and for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. 8 The 10 mg dose is approved for DVT prophylaxis in patients undergoing hip or knee replacement surgery and has near complete absorption (80 100% absolute bioavailability) that is not affected by food. 9 The half-life of rivaroxaban ranges from 5 to 13 hours in healthy subjects. 8 Dysphagia (difficulty swallowing food or liquids) is associated with many health conditions and complications may include aspiration pneumonia, dehydration, or malnutrition. In the United States, dysphagia is estimated to affect more than 18 million adults. More than 40% of 1 Global Clinical Pharmacology, Janssen Research and Development, LLC, Titusville, NJ, USA 2 Janssen Research and Development, LLC, Raritan, NJ, USA 3 Janssen Scientific Affairs, LLC, Raritan, NJ, USA Submitted for publication 17 April 2013; accepted 20 March 2014 Corresponding Author: Larry E. Fields, Janssen Scientific Affairs, LLC 1000 Route 202, Box 300 Raritan, NJ 08869, USA (e mail: lfields@its.jnj.com) Results were presented at the 2012 Annual Meetings of the American College of Clinical Pharmacy and the American Society of Consultant Pharmacists.

2 322 Clinical Pharmacology in Drug Development 3(4) adults in a general community setting self-reported difficulty swallowing pills and of these individuals, 14% delayed taking a medication dose and 8% skipped a dose entirely. 10 Thus, the fact that a tablet may be crushed and administered orally mixed in food or provided as a water suspension via a nasogastric (NG) tube provides an important alternative method of drug administration for these patients. 11,12 However, crushing a tablet and administering it as a suspension might alter the pharmacokinetics of the compound. Additionally, administering a suspension via an NG tube may alter the amount of drug delivered to the GI tract due to drug adsorption onto the luminal surface of the tube. Accordingly, the objectives of these studies were to determine the in vitro stability and NG-tube adsorption characteristics of rivaroxaban and its in vivo relative bioavailability when administered orally as a whole tablet, a crushed tablet mixed with applesauce, or a crushed tablet water suspension delivered via an NG tube. Methods In Vitro Assessment These experiments were essential for the determination of whether to proceed with an assessment in humans and to ascertain the potential suitability of multiple types of crushed tablet suspensions for this new approach. The in vitro stability/adsorption studies were performed by the Department of Pharmaceutical Development & Manufacturing Sciences (PDMS), Janssen Research & Development, in Titusville, NJ. To assess stability, a 20 mg rivaroxaban tablet was crushed into a fine powder, and triplicate samples (sufficient due to low observed variability) were suspended in water (50 ml), orange juice (50 ml), cranberry juice (50 ml), or mixed into applesauce (70 ml), respectively, as a way to model realworld use (e.g., water for patients with an NG tube; or either food for patients who can swallow but have difficulty with whole tablets). Samples were analyzed for rivaroxaban concentration at time 0 (control), 0.5, 1, 2, and 4 hours using a validated HPLC coupled to tandem mass spectrometry (liquid chromatography mass spectrometry [LC MS/MS]) method. 13 NG tube compatibility (extent of degradation or adsorption of rivaroxaban from a suspension onto the inner surface of an NG tube) was assessed for polyvinyl chloride (PVC; Argyle TM Salem Sump TM Tube; Covidien; Mansfield, MA) and silicone (Argyle TM Silicone Salem Sump TM tube; Tyco) tubes. A 20 mg rivaroxaban tablet was crushed to a fine powder, and triplicate samples were suspended in 50 ml of water. The resulting suspension was then either not passed through (control) or passed through (PVC or silicone) NG tubing, which had been pre-rinsed with 20 ml of water. The amount of recovered rivaroxaban was measured by HPLC before (0 hour, baseline) and after (at 0.5, 1, 2, and 4 hours) exposure to NG tubing that was rinsed twice with 65 ml of water. In Vivo Assessment This study was designed by a multidisciplinary team that included members from Janssen Medical and Scientific Affairs, PDMS, Clinical Pharmacology and Research and Development Groups and performed in collaboration with Celerion (Neptune, NJ). An institutional review board (Chesapeake Research Review, Inc., Columbia, MD) approved the protocol and informed consent form before study initiation (Registration No. NCT , last accessed on July 19, 2013 at: Study Subjects To be eligible for randomization, each subject had to be between 18 and 55 years of age (inclusive); healthy (as determined by a study physician using vital sign, medical history, physical examination, 12-lead electrocardiogram [ECG] and clinical laboratory test information); a nonsmoker for at least 3 months; have a body weight 50 kg and a body mass index (BMI) between 18 and 30 kg/m 2 (inclusive); and have provided written informed consent (provided before the initiation of any study-related activity). Subjects who used any prescription or nonprescription medication (except for acetaminophen, oral contraceptives, and hormonal replacement therapy) were excluded, as were those with a history of drug or alcohol abuse. Female subjects who were pregnant or breast-feeding at screening were not eligible for study participation. Study Design This was a phase 1, single-center, open-label, randomized, three-period, three-treatment crossover study conducted in the United States from November 2011 to December Eligible subjects were randomized into one of six pre-specified dosing sequences. Each dosing sequence was comprised of three separate 4-day treatment periods. To minimize potential carryover effects from the previous treatment period, each treatment period was separated by a washout period comprised of a minimum of 6 days to a maximum of 14 days. On Day-1 of each treatment period, a single 20 mg dose of rivaroxaban was administered as either a whole tablet orally as the reference (Whole-Oral), a crushed tablet in applesauce suspension orally (Crushed-Oral), or a crushed tablet in water suspension administered via a 12 Fr PVC NG tube (Crushed-NG; tube from BARD Medical, Covington, GA). Administration of study drug occurred during the morning following an overnight fast. A pre-defined standardized meal (Osmolite Cal) was administered following each 20 mg rivaroxaban dose to optimize bioavailability, reduce variability, and permit

3 Moore et al 323 use across all dosing strategies. This approach is consistent with the approved real-world rivaroxaban (Xarelto 1 ) prescribing information for this dose. For example, real world patients requiring the Crushed-NG tube dosing strategy will very likely not be following the dose with a solid meal. Additionally, patients requiring the Crushed-Oral dosing strategy with applesauce will likely be consuming a soft-solid and/or liquid meal but not a regular solid meal. Rapidly following Reference dosing (Whole-Oral), each subject consumed applesauce (70 ml) and water (130 ml). As soon as possible after applesauce and water consumption, 100 ml of a standardized liquid meal (Osmolite Cal) was administered at 0, 0.5, 1, 1.5, and 2 hours post-dosing (a total of 500 ml of Osmolite post-dosing). The Crushed-Oral dose was prepared shortly before administration by a pharmacist or a qualified designee using a mortar and pestle to crush the 20 mg rivaroxaban tablet. Care was taken to minimize loss of rivaroxaban powder during grinding and transfer from the mortar to applesauce (70 ml). The resulting rivaroxaban in apple sauce suspension was mixed vigorously for approximately 30 seconds and then consumed by the subject. Rapidly following Crushed-Oral dosing, the mortar and pestle was rinsed twice with water (65 ml) to ensure recovery of the full dose. This total rinse volume (130 ml) was then consumed by the subject and followed by consumption of Osmolite (500 ml total volume as detailed above) for the Reference (Whole-Oral) dosing. Just prior to Crushed-NG dosing, an NG tube was inserted. Intragastric placement of the NG tube was confirmed by positioning a stethoscope over the left upper quadrant of the abdomen and injecting air (20 ml) during auscultation. Water (20 ml) was then injected into the NG tube to pre-wet and prime the lumen. Applesauce (70 ml) was not administered during Crushed-NG dosing to avoid NG tube obstruction. A 20 mg rivaroxaban tablet was crushed and transferred as described above, mixed in 50 ml of water for approximately 30 seconds and then administered via the NG tube. Drug administration was followed by consumption of two 15 ml mortar and pestle water rinses (30 ml total volume) to ensure administration of the entire dose. Osmolite (500 ml total volume) was then administered as detailed above for Reference and Crushed-Oral administrations. To ensure that the full amount of Osmolite was delivered during Crushed-NG dosing, each Osmolite administration was followed by a 20 ml water NG tube rinse (100 ml total volume). The NG tube was removed 1 hour after administration of the last liquid meal. To minimize potential volume-related variability across treatment arms, the final total administered volume (700 ml) was the same for the Reference (Whole-Oral), Crushed-Oral and Crushed-NG dosing. Each subject received the same volume of water (130 ml) and Osmolite (500 ml) after each drug administration. Applesauce (70 ml) was only administered during Reference (Whole-Oral) and Crushed-Oral dosing. However, during Crushed-NG dosing, the total volume (70 ml) for NG tube water pre-wetting/priming (20 ml) and rivaroxaban water suspension (50 ml) was the same as the total applesauce volume (70 ml). Pharmacokinetic Assessment Blood samples (4 ml, each) for the determination of plasma rivaroxaban concentrations were collected at predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 15, 24, 36, and 48 hours after dosing and centrifuged at room temperature. Plasma samples were stored at approximately 20 C and later analyzed for rivaroxaban concentration at the Department of Drug Metabolism and Pharmacokinetics at Bayer Pharma AG (Wuppertal, Germany) using validated LC MS/MS methodology. 13 The following key pharmacokinetic parameters were determined via non-compartmental methods for each treatment: Area under the curve from time 0 to time of the last quantifiable concentration (AUC last ), from time 0 to 48 hours (AUC 0 48 h ), and from time 0 to time infinity (AUC 1 ), maximum plasma concentration (C max ); time to maximum plasma concentration (t max ), and apparent elimination half-life associated with the terminal slope (lz) of the semi-logarithmic drug concentration-time curve (t 1/2,lz ). Safety and Tolerability Assessment Safety and tolerability were assessed throughout the study using symptom, vital sign, physical examination, 12-lead ECG, clinical laboratory test (hematology, clinical chemistry, coagulation [prothrombin time, activated partial thromboplastin time], and pregnancy) information, and spontaneously reported or observed adverse events. Statistical Methods Sample Size. The sample size calculation was based on the AUC for rivaroxaban as the primary pharmacokinetic endpoint. Using an estimated intrasubject coefficient of variation of 20% for the AUC and C max of rivaroxaban, a sample size of 42 subjects completing the study was considered to be sufficient to ensure that the point estimate of the relative bioavailability of rivaroxaban fell within % of the true ratio with 90% confidence. The 20% CV was assumed to be in line with relative BA studies, in general; and was not based on any specific study. Analysis Populations. All randomized subjects with any pharmacokinetic data, whether the subject completed the study or not, were included in the overall pharmacokinetic analysis set, and the subset of those who received study drug using all three dosing strategies (Reference

4 324 Clinical Pharmacology in Drug Development 3(4) [Whole-Oral], Crushed-Oral, and Crushed-NG) and who completed the study as specified in the study protocol were included in a pharmacokinetic analysis data set. The safety analysis data set included all subjects who received at least one dose of rivaroxaban. Statistical Analyses. Demographic and baseline characteristics were summarized for the safety analysis data set. Descriptive statistics of pharmacokinetic parameters are presented by each treatment using the overall pharmacokinetic analysis data set. AUCs (AUC 0 48, AUC last, and AUC 1 ) and C max from the pharmacokinetic analysis data set were analyzed by analysis of variance (ANOVA). While not a formal bioequivalence study, Reference, Crushed-Oral, and Crushed-NG dosing were considered bioequivalent if the ratios of geometric least squares means and associated 90% confidence intervals (CIs) were within the % range. Results In Vitro Assessment Rivaroxaban was stable as a crushed tablet in water, juice, and applesauce suspensions for up to 4 hours. There was no significant change in the mean percent (relative standard deviation [RSD]) of non-degraded rivaroxaban recovered over the 4-hour period for each of the crushed tablet suspensions (at time 0 mean percents [RSDs] ranged from 98.5% to 100.7% [0.2% to 0.4%). For adsorption, the mean percent (RSD) of non-degraded rivaroxaban recovered after NG tube exposure was 98.8% (0.4) for control, 99.1% (0.2) for silicone tubing, and 98.9% (0.2) for PVC tubing. In Vivo Assessment Subjects. Among the 55 randomized subjects, the baseline characteristics were well balanced across the six treatment sequences. The median age was 39, ranging from 24 to 53 years of age. The majority of subjects were male (42 [76.4%]) and Black (27 [49.1%]) or White (24 subjects [43.6%]). The median weight was 78.5 kg (range, 55 99) and median BMI was 25.9 kg/m 2, (range, ). Forty-five of the 55 subjects randomized (82%) completed the study. The reasons for discontinuation from the study included: withdrawal of consent (4 [7.3%]); adverse events (2 [3.6%]; pre-existing multiple sclerosis and vomiting), protocol violation (2 [3.6%]; positive drug screen), lost to follow-up (1 [1.8%]), and technical problems (1 [1.8%]; unable to tolerate NG tube insertion). Due to a randomization error, one subject was excluded from the statistical analysis. Inclusion of this subject as a sensitivity analysis did not alter the results. Thus, 44 subjects were included in the final ANOVA analysis. Pharmacokinetics. Both Crushed-Oral and Crushed- NG dosing showed a slightly faster onset of absorption in comparison with Reference (Whole-Oral) dosing (Figure 1). The rivaroxaban concentration-time profile of 48 (98.0%) of the 49 subjects that received the Crushed-NG dosing displayed a double peak. The first peak generally occurred approximately 45 minutes after dosing. The second peak occurred 4 6 hours after dosing, which was consistent with the time of peak plasma concentrations observed with the Reference and Crushed- Oral dose administrations. Rivaroxaban t max, AUC, and t 1/2 values were similar across the three different dosing strategies, while C max for Crushed-NG dosing was slightly lower (Table 1). The 90% CI for the ratio of geometric means for C max and AUC values when comparing rivaroxaban 20 mg Crushed-Oral with Reference dosing were contained within the bioequivalence limits of % (Table 2). Similarly, the 90% CI for the ratio of geometric means for AUC values when comparing rivaroxaban 20 mg Crushed-NG with Reference dosing were also contained within the bioequivalence limits of %. The lower boundary of the 90% CI of the ratio of the geometric means for C max (78.5%) fell slightly outside the bioequivalence limits. Safety Results. Twenty-five (45.5%) subjects reported at least one treatment-emergent AE. The most commonly reported AEs were headache, dizziness, and vomiting. Individual reports on the four subjects with vomiting were reviewed. There was no evidence that individual PK parameters were affected. Specifically, all vomiting events occurred post-dose. One subject discontinued. The second subject vomited >24 hours post-dose. The third and fourth subjects vomited approximately Figure 1. Mean (SE) plasma rivaroxaban concentration time profiles following administration of rivaroxaban (linear linear) (overall pharmacokinetic analysis data set).

5 Moore et al 325 Table 1. Mean (SD) Plasma Rivaroxaban Pharmacokinetic Parameters on Day 1 by 20 mg Formulation (Overall Pharmacokinetics Analysis Data Set) Rivaroxaban 20 mg formulation Pharmacokinetic parameters Reference Crushed Oral Crushed NG n Mean a SD n Mean a SD n Mean a SD C max (ng/ml) t max (hours) b ( ) ( ) ( ) AUC last (ng h/ml) AUC 0 48 h (ng h/ml) AUC 1 (ng h/ml) c t1/2,term (hours) c a Arithmetic mean. b Median and range. c Additional analysis performed with a n ¼ 48, as one subject had r 2 < 0.8 for the terminal slope, and was excluded from descriptive statistics for AUC 1 and t 1/2.AUC last ¼ from time 0 to time of the last quantifiable concentration; AUC 0 48 h ¼ from time 0 to 48 hours; AUC 1 ¼ from time 0 to infinite time; C max ¼ time to maximum plasma concentration; h ¼ hour; t max ¼ time to C max ;t1/2,term ¼ terminal half life. 40 minutes and 2 hours post-dose, respectively; however, the time-concentration profile and PK parameters did not substantially differ from mean values. No imbalance of other AEs, including nausea, was noted across dosing strategies. No bleeding events were reported. All treatment-emergent AEs were classified as mild or moderate in severity, and none were considered to be very likely, probably, or possibly related to the study drug. As mentioned above, two subjects discontinued study participation prematurely because of AEs. No clinically significant abnormalities were reported for vital signs, physical examinations, ECGs, or laboratory values. Discussion Crushing a tablet and administering it mixed in food is a common and convenient method for administering medications to patients who have difficulty swallowing, Table 2. Geometric Mean Treatment Ratios (%) and Associated 90% Confidence Intervals (Pharmacokinetics Analysis Data Set) Pharmacokinetic parameters Reference formulation Crushed oral formulation Ratio (%) 90% CI n Geometric mean n Geometric mean C max (ng/ml) AUC last (ng h/ml) AUC 0 48 h (ng h/ml) AUC 1 (ng h/ml) a Reference formulation Crushed NG formulation Pharmacokinetic parameters n Geometric mean n geometric mean Ratio (%) 90% CI C max (ng/ml) AUC last (ng h/ml) AUC 0 48 h (ng h/ml) AUC 1 (ng h/ml) a AUC last, from time 0 to time of the last quantifiable concentration; AUC 0 48 h, from time 0 to 48 hours; AUC 1, from time 0 to infinite time; C max, time to maximum plasma concentration. a Additional ANOVA performed with a n ¼ 43, as one subject had r 2 < 0.8 for the terminal slope, and was excluded from inferential statistics for AUC 1.

6 326 Clinical Pharmacology in Drug Development 3(4) have confusion or memory loss. 14 However, crushing a medication may alter its chemical structure or pharmacokinetic characteristics. Enteral feeding tubes are frequently used to administer food and medication to patients who cannot swallow safely. 15 For patients who require only short-term enteral feeding, nasoenteric feeding tubes are commonly used, because they are easier to place and are less costly than other enteral access routes. These feeding tubes may be inserted nasally, with the distal end of the tube in the stomach (NG), or via other routes (e.g., gastrostomy when a tube cannot be placed nasally because of head injury or sinusitis). Gastric access is generally preferred over jejunal administration, because gastric tubes are larger and less prone to clogging, and because the stomach may be more tolerant of, for example, hypertonic medications. However, there is always a concern that using enteral feeding tubes to deliver medication may alter the amount of drug actually delivered to the GI tract, because of the potential for drug adsorption to the tubing. A single 20 mg dose of rivaroxaban was selected for testing in both the in vitro and in vivo studies, because it represents the highest single dose administered across approved indications. To determine whether to proceed with human studies, we assessed the in vitro stability and NG tube adsorption characteristics of a crushed 20 mg rivaroxaban tablet in various food and beverage suspensions. The results of which show that rivaroxaban did not adsorb to the NG-tubing and that the crushed rivaroxaban tablet remained stable for up to 4 hours in the suspensions tested. Further in vitro evaluation of crushed rivaroxaban tablets was subsequently assessed for both the 10 and 2.5 mg dose strengths. Stability and adsorption results were similar to those observed for the 20 mg tablet, thus confirming our original assumption that results from the 20 mg tablet studies are generally applicable across a wide range of rivaroxaban dose strengths. In the human relative bioavailability study, rivaroxaban mean C max and AUC parameters for the Crushed- Oral dosing were similar (bioequivalence criteria met) to those values for Reference dosing. For the Crushed-NG dosing, rivaroxaban mean AUC was similar (bioequivalence criteria met), while rivaroxaban C max was 18% lower compared to Reference dosing. The lower C max value is not considered clinically significant based on considerations that include previous exposure-response analysis. 16 This is the first NG tube-based rivaroxaban pharmacokinetic study. The mean plasma concentration-time profile and pharmacokinetic parameters of rivaroxaban after Reference (Whole-Oral) dosing are consistent with results observed in previous healthy subject clinical pharmacology studies. 7 For Crushed-Oral dosing, the mean plasma concentration-time profile showed a slightly more rapid onset of absorption through the first 3 hours post dose, but a similar profile thereafter, relative to Reference dosing. Similar to the Crushed-Oral dosing, the mean plasma concentration-time profile for the Crushed-NG dosing showed a slightly more rapid onset of absorption through the first hour post dose. However, median t max values were similar for all three groups. The finding of a double peak following Crushed-NG dosing was not observed in previously conducted non-ng tubebased clinical pharmacology studies. While an exact explanation for this profile is not known, there are several potential factors that may have contributed to this result: (1) upon crushing the tablet and suspending it in water, the fine drug particles may have dissolved quickly, leading to a more rapid initial phase of absorption; (2) after administering the NG suspension, initial, rapid gastric emptying may have been quickly followed by a slowing of emptying and transit time associated with ingestion of the liquid meal; and/or (3) despite auscultatory confirmation of gastric placement of the NG tube, the distal end of NG tube may have been in close proximity to the pyloric sphincter, such that some of the suspension may have flowed directly into the duodenum, essentially bypassing the stomach, and leading to rapid initial onset of absorption Some potential limitations of this study include the fact that, for practical reasons, only a select number of beverages or foods were tested in vitro. All NG tube placements were intragastric, thus the results from this study are not directly applicable to individuals who have a more distal placement of feeding tubes (e.g., proximal or distal small intestine, or ascending colon). Only water was used for Crushed-NG dosing, although crushedtablet rivaroxaban was shown to be stable in other beverages. In previously conducted studies that assessed the effects of food administration with rivaroxaban, meals were completed within 30 minutes before drug administration, whereas in this trial, a liquid meal was given soon after administration of the study drug). In conclusion, the results of this study support the administration of rivaroxaban as either a crushed tablet mixed in applesauce and taken orally or suspended in water and administered via an NG tube. These new alternative methods of rivaroxaban administration provide important options for patients with difficulty swallowing. Acknowledgments Thanks to Gabriele Rohde and Christa Schuettler, Bayer Healthcare Bioanalytics, who performed the rivaroxaban plasma concentration analysis and prior validation of LC MS/MS methodology (GR); to Jean Farrell and the global clinical operations team for assistance with study coordination and project management; to John Anderson and Mae Kwong for assistance with project management; to Sandra Norris for assistance with initial drafting, Behin Yektashenas, and

7 Moore et al 327 Michelle Gearhart for assistance with publication planning and George Fuller for assistance with editing and publication submission. Declaration of Conflicting Interests All authors are employees of Janssen Research & Development, LLC (K.T.M., M.A.K., S.V., T.C.S., C.V.D.) or Janssen Scientific Affairs, LLC (L.E.F.). Funding This study was funded by Janssen Scientific Affairs, LLC. References 1. Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol. 2012;26(1): Perzborn E, Strassburger J, Wilmen A, et al. In vitro and in vivo studies of the novel antithrombotic agent BAY an oral, direct factor Xa inhibitor. J Thromb Haemost. 2005;3(3): Perzborn E, Roehrig S, Straub A, Kubitza D, Misselwitz F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat Rev Drug Discov. 2011;10(1): Cabral KP, Ansell J. Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Nat Rev Cardiol. 2012;9(7): Kubitza D, Becka M, Voith B, Zuehlsdorf M, Wensing G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY , an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4): Kubitza D, Becka M, Wensing G, Voith B, Zuehlsdorf M. Safety, pharmacodynamics, and pharmacokinetics of BAY an oral, direct Factor Xa inhibitor after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12): Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006;46(5): Sarich TC, Peters G, Berkowitz SD, et al. Rivaroxaban: a novel oral anticoagulant for the prevention and treatment of several thrombosis-mediated conditions. Ann N Y Acad Sci. 2013;1291(1): Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther. 2013;51(7): Carnaby-Mann G, Crary M. Pill swallowing by adults with dysphagia. Arch Otolaryngol Head Neck Surg. 2005; 131(11): Cornish P. Avoid the crush : hazards of medication administration in patients with dysphagia or a feeding tube. CMAJ. 2005;172(7): Yuk JH, Nightingale CH, Sweeney KR, Quintiliani R, Lettieri JT, Frost RW. Relative bioavailability in healthy volunteers of ciprofloxacin administered through a nasogastric tube with and without enteral feeding. Antimicrob Agents Chemother. 1989;33(7): Rohde G. Determination of rivaroxaban a novel, oral, direct Factor Xa inhibitor in human plasma by highperformance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2008;872(1 2): Gill D, Spain M, Edlund BJ. Crushing or splitting medications: unrecognized hazards. J Gerontol Nurs. 2012;38(1): Williams NT. Medication administration through enteral feeding tubes. Am J Health Syst Pharm. 2008;65(24): Fisher WD, Eriksson BI, Bauer KA, et al. Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies. Thromb Haemost. 2007;97(6): Davies NM, Takemoto JK, Brocks DR, Yáñez JA. Multiple peaking phenomena in pharmacokinetic disposition. Clin Pharmacokinet. 2010;49(6): Marathe PH, Sandefer EP, Kollia GE, et al. In vivo evaluation of absorption and gastrointestinal transit of avitriptan in fed and fasted subjects using gamma scintigraphy. J Pharmacokinet Biopharm. 1998;26(1): Zhou H. Pharmacokinetic strategies in deciphering atypical drug absorption profiles. J Clin Pharmacol. 2003;43(3):