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A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery.

ABSTRACT: BACKGROUND:Edoxaban is an oral, direct, factor Xa inhibitor approved in Japan for thromboembolic prophylaxis after lower-limb orthopedic surgery (LLOS), but contraindicated in patients with severe renal impairment (SRI; creatinine clearance [CLCR] ?15 to <30 mL/min). METHODS:This open-label study compared the safety of edoxaban 15 mg once daily in Japanese patients with SRI to that of edoxaban 30 mg in patients with mild renal impairment (MiRI; CLCR ?50 to ?80 mL/min; N?=?30) undergoing LLOS. Patients with CLCR ?20 to <30 mL/min were randomized to receive edoxaban 15 mg (N?=?22) or subcutaneous fondaparinux 1.5 mg once daily (N?=?21). All patients with CLCR ?15 to <20 mL/min received edoxaban 15 mg (N?=?7). Treatment was administered for 11 to 14 days. RESULTS:Major or clinically relevant non-major bleeding occurred in 6.7%, 3.4%, and 5.0% of patients in the MiRI edoxaban 30-mg, SRI edoxaban 15-mg, and SRI fondaparinux groups, respectively; there were no major bleeding events. No thromboembolic events occurred. At all time points assessed, edoxaban plasma concentrations and changes in coagulation biomarkers were similar between the SRI and MiRI groups. CONCLUSIONS:These results suggest edoxaban 15 mg once daily is well tolerated in Japanese patients with SRI undergoing LLOS. TRIAL REGISTRATION:Clinicaltrials.gov Identifier: NCT01857583.

SUBMITTER: Fuji T

PROVIDER: S-EPMC4316611 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery.

Fuji Takeshi T Fujita Satoru S Kawai Yohko Y Abe Yasuyuki Y Kimura Tetsuya T Fukuzawa Masayuki M Abe Kenji K Tachibana Shintaro S

Thrombosis journal 20150130 1

<h4>Background</h4>Edoxaban is an oral, direct, factor Xa inhibitor approved in Japan for thromboembolic prophylaxis after lower-limb orthopedic surgery (LLOS), but contraindicated in patients with severe renal impairment (SRI; creatinine clearance [CLCR] ≥15 to <30 mL/min).<h4>Methods</h4>This open-label study compared the safety of edoxaban 15 mg once daily in Japanese patients with SRI to that of edoxaban 30 mg in patients with mild renal impairment (MiRI; CLCR ≥50 to ≤80 mL/min; N = 30) unde ...[more]

PMID: 25653574

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Project description:Background:This study involved a sensory evaluation of edoxaban orally disintegrating (OD) tablets in patients with nonvalvular atrial fibrillation who had been receiving the existing edoxaban film-coated tablets before the study. Methods:Edoxaban OD tablets 30 or 60 mg were prescribed for patients who had been receiving the existing 30- or 60-mg edoxaban film-coated tablets before the study. Each dose group was randomized into groups taking the tablets with or without water. After ingestion of the edoxaban OD tablet, each patient was asked to complete a sensory evaluation questionnaire (12 items). Results:In the evaluation of satisfaction with edoxaban OD tablets, 52.8% of the patients perceived "no difference" from the existing edoxaban film-coated tablets and 34.9% indicated that they were more satisfied with the OD tablets, thus demonstrating a relatively high degree of satisfaction. When asked about convenience and reliability in using edoxaban OD tablets, about half of the patients perceived "no difference" from the existing edoxaban film-coated tablets and the remaining half indicated preference for the OD tablets. Responses about taste, flavor, ease of ingestion, and motivation to continue taking edoxaban indicated the overall acceptance of the OD tablets. Recognition of edoxaban OD tablets was rated as "easy" by about half of the patients and "difficult" by the remaining half. Among all patients, 49.5% preferred a change to edoxaban OD tablets. The degree of satisfaction with taste, flavor, and ease of ingestion, as well as overall satisfaction, tended to be greater when the OD tablets were taken with rather than without water, and the percentage of patients who preferred a change was higher in the group taking the OD tablets with water. Conclusions:This study indicated that the degree of satisfaction with taste, flavor, ease of ingestion, and convenience, as well as overall satisfaction, in addition to motivation to continue drug intake and sense of confidence were greater for OD tablets than for the existing edoxaban film-coated tablets. Edoxaban OD tablet is a promising formulation for inducing greater patient adherence to medication and therefore ensures better treatment response. Trial registration:UMIN-CTR UMIN000028788, registered 23-Aug-2017.

Project description:BackgroundZibotentan (ZD4054) is a specific endothelin A (ETA) receptor antagonist being investigated for the treatment of prostate cancer. As zibotentan is eliminated by renal and metabolic routes, clearance may be reduced in patients with hepatic or renal impairment, leading to greater drug exposure.MethodsOpen-label studies investigated the PK and tolerability of zibotentan in subjects with hepatic or renal impairment, compared with those with normal organ function. In the hepatic and renal studies, respectively, subjects were divided into categories using Child-Pugh classification or 24-hour urine creatinine clearance (mild, moderate, or severe impairment and normal function). Each subject received a single oral dose of zibotentan 10 mg and PK sampling was undertaken. Within the hepatic study, AUC and Cmax were expressed as the ratio of geometric means and 90% CI for each impairment group compared with the normal function group. The possibility that hepatic impairment had a clinically relevant effect on exposure was considered if the upper 90% CI for the ratio exceeded 2. In the renal study, AUC, Cmax and t1/2 were analyzed using linear regression fitting effects for creatinine clearance and age.ResultsIn the hepatic and renal studies respectively, 32 subjects (eight per group) and 48 subjects received treatment (n = 18 normal, n = 12 mild, n = 9 moderate, n = 9 severe). Zibotentan Cmax was not significantly affected by hepatic or renal impairment. Compared with the normal function group, zibotentan AUC was 40% (1.40; 90% CI 0.91-2.17), 45% (1.45; 90% CI 0.94-2.24) and 190% (2.90; 90% CI 1.88-4.49) higher in subjects with mild, moderate and severe hepatic impairment, respectively, and 66% (1.66; 90% CI 1.38-1.99), 89% (1.89; 90% CI 1.50-2.39) and 117% (2.17; 90% CI 1.64-2.86) higher in subjects with mild, moderate and severe renal impairment, respectively. In both studies mean t1/2 increased and zibotentan clearance decreased with the degree of impairment. Headache was the most common AE in all groups.ConclusionsZibotentan absorption was unchanged, however, exposure was higher in subjects with hepatic or renal impairment due to slower clearance. This increased exposure did not result in differences in the range or severity of AEs observed.Trial registrationClinicalTrials.gov: NCT00672581 and AstraZeneca study number D4320C00016 (renal trial; conducted in Germany).

Dataset Information

A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery.

Publications

A randomized, open-label trial of edoxaban in Japanese patients with severe renal impairment undergoing lower-limb orthopedic surgery.

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