In 24 participants for safety analysis (prasugrel 2.5 mg group: n=12, prasugrel 3.75 mg group: n=12), mean age (mean +- standard deviation) was 72 +- 4 years, and 16 participants (66.7%) were 65~ <75 years old, 8 participants (33.3%) were 75~80 years old. In prasugrel 2.5 mg and 3.75 mg groups, ages were 71 +- 4 years and 73 +- 3 years, respectively.
The height was 164.0 +- 5.7 cm in all participants, 162.5 +- 5.7 cm in the prasugrel 2.5 mg group, and 165.5 +- 5.6 cm in prasugrel 3.75 mg group.
Body weight was 56.4 +- 2.2 kg in all participants and 50 <~60 kg in 24 participants (100.0%). In prasugrel 2.5 mg and 3.75 mg groups, body weight were 55.8 +- 2.4 kg and 57.0 +- 1.9 kg, respectively.
BMI was 21.1 +- 1.6 kg/m2 in all participants, 21.3 +- 1.6 kg/m2 in prasugrel 2.5 mg group, and 21.0 +- 1.6 kg/m2 in prasugrel 3.75 mg group.
eGFR was 73.5 +- 7.0 mL/min/1.73m2 in all participants, and 60~<90 mL/min/1.73m2 in 24 participants (100.0%). In prasugrel 2.5 mg and 3.75 mg groups, eGFR were 75.5 +- 6.6 mL/min/1.73m2 and 71.6 +- 7.1 mL/min/1.73m2, respectively.
Ccr was 67.2 +- 7.2 mL/min in all participants, and 50 mL/min~ in 24 participants (100.0%). In prasugrel 2.5 mg and 3.75 mg groups, 68.7 +- 6.1 mL/min and 65.8 +- 8.1 mL/min, respectively.
There were medical histories in 14 participants (58.3%) out of all 24 participants.
In this study, informed consent was obtained from 65 subjects, 24 of whom were randomly assigned to prasugrel 2.5 mg group and prasugrel 3.75 mg groups (12 participants each). All 24 participants received all of the study drugs in accordance with the study design. Since, all 24 study participants completed the study.
All 24 randomized study participants (prasugrel 2.5 mg group: n=12, prasugrel 3.75 mg group: n=12) had included in safety analysis, bleeding time analysis, and pharmacokinetic and pharmacodynamic analysis.
Adverse events were observed in 3 participants (25.0%) in stage I (edoxaban alone) and 7 participants (58.3%) in stage II (edoxaban + prasgurel) in prasgurel 2.5 mg group, and 3 participants (25.0%) in stage I and 7 participants (58.3%) in stage II in prasgurel 3.75 mg group.
The breakdown of adverse events was as follows: Constipation was observed in 1 participant each in stage I of the prasugrel 2.5 mg group and stage I and stage II of the prasugrel 3.75 mg group (8.3%).
Fecal occult blood was observed in 2 participants (16.7%) in stage I and 7 participants (58.3%) in stage II in prasugrel 2.5 mg group. There were 2 participants (16.7%) in stage I and 7 participants (58.3%) in stage II in prasugrel 3.75 mg group.
All of these adverse events were non-serious and confirmed recovery without treatment. Fecal occult blood was judged to be a side effect because the causal relationship with the study drugs could not be ruled out.
There were no serious adverse events, serious side effects, or adverse events leading to discontinuation.
Bleeding time (Primary endpoint)
After 3 days of a once-daily dosing of 30 mg edoxaban, the GLSMs of bleeding time ratios to baseline were 1.097 (90% CI 0.911 ~ 1.321) in prasugrel 2.5 mg group and 1.327 (90% CI 1.035 ~ 1.703) in prasugrel 3.75 mg group. After the coadministration of edoxaban and prasugrel for 5 days, bleeding time was further prolonged. Especially in prasugrel 3.75 mg group, bleeding time was continued over 10 minutes in 5 out of 12 subjects. The GLSMs of bleeding time ratios were 1.581 (90% CI 1.197 ~ 2.087) in prasugrel 2.5 mg group and 1.996 (90% CI 1.482 ~ 2.690) in prasugrel 3.75 mg group. The GLSM increases in bleeding time by prasugrel (edoxaban plus prasugrel/edoxaban alone) were 1.442 (90% CI 1.096 ~ 1.897) in prasugrel 2.5 mg group and 1.504 (90% CI 1.172 ~ 1.930) in prasugrel 3.75 mg group.
Pharmacokinetics(Secondary endpoint)
As pharmacokinetic parameters, Cmax, ss (mean +- standard deviation) were 216.0 +- 112.4 ng / mL in stage I and 216.0 +- 80.4 ng / mL in stage II in prasugrel 2.5 mg group, and 191.4 +- 79.7 ng / mL in stage I and 216.9 +- 68.1 ng / mL in stage II in prasugrel 3.75 mg group. AUCtau, ss (mean +- standard deviation) were 1059.4 +- 228.0 ng h / mL in stage I and 1068.6 +- 189.8 ng h / mL in stage II in prasugrel 2.5 mg group, and 1070.4 +- 239.7 ng h / mL in stage I and 1088.5 +- 223.2 ng h / mL in stage II in prasugrel 3.75 mg group. tmax, ss [median (range)] were 0.75 (0.50 ~ 3.0) h in stage I and 0.75 (0.50 ~ 3.0) h in stage II in prasugrel 2.5 mg group, and 0.50 (0.50 ~ 3.0) h in stage I and 0.50 (0.50 ~ 1.0) h in stage II in prasugrel 3.75 mg group.
In addition, for Cmax, ss and AUCtau, ss, the ratios of prasugrel combination versus edoxaban alone were calculated.
The ratios of Cmax, ss [geometric least mean square (90% confidence interval)] were 1.075 (0.857 ~ 1.348) in prasugrel 2.5 mg group and 1.170 (1.002 ~1.365) in prasugrel 3.75 mg group.
The ratios of AUCtau, ss were 1.017 (0.960 ~ 1.078) in prasugrel 2.5 mg group and 1.019 (0.988 ~ 1.052) in prasugrel 3.75 mg group.
Pharmacodynamic parameters of coagulation and platelet aggregation(Secondary endpoint)
The administration of 30 mg edoxaban prolonged PT, in sec, from a mean of 11.8 at baseline to 15.3 in prasugrel 2.5 mg group and 11.9 at baseline to 15.5 in prasugrel 3.75 mg group. With the addition of 2.5 mg or 3.75 mg prasugrel, the PT values were essentially unchanged in both groups (mean of 15.2 and 15.1). aPTT, in sec, was also prolonged by edoxaban from 31.9 at baseline to 38.0 in prasugrel 2.5 mg group and 34. 2 at baseline to 39.9 in prasugrel 3.75 mg group. Again, the effect of edoxaban on aPTT was unchanged (mean of 37.7 and 39.1) by addition of 2.5 mg or 3.75 mg prasugrel. Edoxaban decreased F1+2, in pmol/L, from 309 at baseline to 112 in prasugrel 2.5 mg group and 279 at baseline to 129 in prasugrel 3.75 mg group. F1+2 were essentially unchanged (mean of 123 and 120) by addition of 2.5 mg or 3.75 mg prasugrel. In the platelet aggregation assay, edoxaban essentially had no effect on PRU. After 2.5 mg and 3.75 mg prasugrel was administered, PRU was reduced from a mean of 249 at baseline to 158 and 246 at baseline to 78, respectively.
In Japanese healthy elderly male subjects, coadministration of 2.5 mg and 3.75 mg prasugrel, a P2Y12 receptor inhibitor, with 30 mg edoxaban, a direct oral anticoagulant, prolonged bleeding time. Effect on bleeding time was dependent on the doses of prasugrel.
Prasugrel had no effect on the pharmacokinetics of edoxaban.
Edoxaban prolonged PT and aPTT and decreased F1+2, whereas prasugrel had no effect on these pharmacodynamics of edoxaban. Prasugrel reduced PRU, but edoxaban did not affect PRU.
2020年01月24日
3 IPDシェアリング
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無
No
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N/A
N/A
管理的事項
研究の種別
特定臨床研究
届出日
令和2年2月18日
臨床研究実施計画番号
jRCTs071190006
1 特定臨床研究の実施体制に関する事項及び特定臨床研究を行う施設の構造設備に関する事項
(1)研究の名称
エドキサバンとプラスグレル併用時の臨床薬理研究
The effects of Prasugrel on pharmacokinetics and pharmacodynamics of Edoxaban (None)
エドキサバンとプラスグレル併用時の臨床薬理研究
The effects of Prasugrel on pharmacokinetics and pharmacodynamics of Edoxaban (None)
1) Japanese elderly men 2) Gained written consent before the screening test 3) 65 years old or older, younger than 80 years old (at obtaining the informed consent) 4) Body weight is greater than 40 kg and 60 kg or less and whose BMI is 18.5 kg/m2 or more and less than 25.0 kg/m2 5) Quit smoking during the hospital stay
1) Person who judged by investigator etc. that research implementation is problematic in terms of ensuring safety because of disorders such as central nervous system, cardiovascular system, respiratory system, blood / hematopoietic function system, digestive system, liver / kidney function, thyroid function, pituitary function, adrenal function and the like or their past history. 2) Hypersensitivity or idiosyncrasy (Penicillin allergy etc.) to drug etc. 3) Alcohol or drug dependents 4) Positive for one or more of HBs antigen, syphilis test (RPR, TP antibody), HCV antibody, HIV antigen antibody in infectious disease test. 5) Confirmed positive findings in fecal occult blood test or urinary occult blood test. (at screening tests) 6) Bleeding diathesis (Easy to bleed from nasal mucosa or oral mucosa, etc.)(at screening tests) 7) Hemorrhagic diseases (intracranial hemorrhage, gastrointestinal bleeding, vitreous hemorrhage, retinal bleeding, hemoptysis, hematemesis, hematuria, bloody stools, hemorrhoids, hemorrhoid diseases, etc.)(tests at Screening and the time of hospitalization) 8) Has a family history (Up to the second degree of kinship of Direct family) of hereditary hemorrhagic disease. (Such as hemophilia, Von Willebrand disease, factor VII deficiency, factor X deficiency, factor XI deficiency, platelet dysfunction etc.)(at screening tests) 9) Bleeding time exceeds 9.5 minutes. However, excluding those who have judged that investigator etc. have no problem in participating in the research at the time of hospitalization tests. 10) Prothrombin time (PT) exceeding the facility reference value upper limit, or extension of activated partial thromboplastin time (aPTT). (tests at Screening and the time of hospitalization) 11) Received medical practice (including mental trauma, dental treatment by dentist) from other doctors within 14 days before hospitalization tests. However, excluding those who have judged that investigator etc. have no problem in participating in the research at the time of hospitalization tests. 12) Surgery is planned during the research period. (at screening tests) 13) One of the following.
More than 800 mL of whole blood was collected within 1 year before a screening tests. More than 400 mL of whole blood was collected within 84 days before a screening tests. More than 200 mL of whole blood was collected within 28 days before a screening tests. Blood component was collected within 14 days before a screening tests. Whole blood collection and component blood collection after the screening test (Blood collection done in this research, or excluding cases where investigetor etc. deems it necessary). 14) Participated in other research within 120 days prior to the screening tests and took study drugs. 15) A person who took or ingested an inhibitor or inducer of the drug metabolizing enzyme CYP3A4, or inhibitor of P-glycoprotein ithin 30 days before administration of the study drug or a person who intends to take it or intake it. (tests at Screening and the time of hospitalization) 16) Used other medicine within 7 days before hospitalization tests. 17) Ingested citrus fruits and their processed products within 7 days before hospitalization tests. 18) Laboratory test value deviates from the standard value of the medical institution, Abnormalities in electrocardiogram examination or There are clinically problematic symptoms / findings. (tests at Screening and the time of hospitalization) 19) eGFR level is less than 60mL/min/1.73m2. (tests at Screening and the time of hospitalization) 20) In addition, those who judged that investigator etc. is inappropriate. (When it is expected that adherence to visit or medication is difficult)