Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation.
Purpose: The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure-response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF). Methods: Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phas...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 70; no. 11; pp. 1339 - 1352 |
|---|---|
| Autores principales: | , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Springer Nature
Nov2014
|
| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=103903846&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 103903846 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Nov2014 vid: 70 iid: 11 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 103903846 98899878 10.1007/s00228-014-1736-4 NLM25168620 103903846 ppf: 1339 ppct: 13 formats: fmt: @attributes: type: P tig: atl: Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation. aug: au: Yin, Ophelia Tetsuya, Kimura Miller, Raymond affil: Modeling and Simulation Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, 399 Thornall Street Edison 08837 USA sug: subj: Atrial Fibrillation Classification Atrial Fibrillation Drug Therapy Anticoagulants Administration and Dosage Anticoagulants Pharmacokinetics Human Biological Availability Kidney Diseases Etiology Hemorrhage Diagnosis Hemorrhage Etiology Kidney Diseases Diagnosis Anticoagulants Adverse Effects Descriptive Statistics Metabolic Clearance Rate Quinidine Administration and Dosage Drug Therapy, Combination Adult Middle Age Aged Aged, 80 and Over Male Female Data Analysis Software Logistic Regression Confidence Intervals Adult: 19-44 years Middle Aged: 45-64 years Aged: 65+ years Aged, 80 & over Male Female ab: Purpose: The aim of this study was to evaluate the population pharmacokinetics (PK) and exposure-response relationship of edoxaban in patients with non-valvular atrial fibrillation (AF). Methods: Concentration data from 1,134 subjects in 11 clinical studies (eight phase I, one phase II, and two phase III) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein (P-gp) inhibitors as well as renal impairment on edoxaban PK. The potential relationship between edoxaban PK exposure and incidence of bleeding events was explored based on data from 893 AF patients. Results: Absolute bioavailability of edoxaban was estimated as 58.3 %. With oral dosing of edoxaban, co-administration of various P-gp inhibitors significantly increased edoxaban bioavailability and decreased volume of distribution ( V), resulting in a predicted increase of 33-77 % in area under the curve (AUC) and 65-104 % in C. A much smaller increase was seen in edoxaban concentration at 24 h post-dose ( C, −24 to 38 %), due to decreased V and shortened elimination half-life. With IV dosing of edoxaban, co-administration of the P-gp inhibitor quinidine decreased both edoxaban clearance (CL) and V, resulting in an increase of 32 % in AUC and 66 % in C. Creatinine clearance was a significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Model-predicted steady state C was slightly higher, but AUC was comparable for patients who had severe renal impairment and received edoxaban 15 mg once daily (QD) versus patients who had normal renal function or mild renal impairment and received edoxaban 30 mg QD. Exposure-response analysis suggested that edoxaban C and country/region are significantly associated with the incidence of bleeds. Conclusions: The model provided reasonable estimation with regard to the absolute bioavailability of edoxaban, the magnitude of change in edoxaban exposure upon co-administration of P-gp inhibitors, and the impact of renal impairment on edoxaban clearance. Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. Further confirmation will be sought by incorporating clinical safety and efficacy information from larger phase III trials. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
|---|