Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation.

Abstract:

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 2), resulting in a predicted increase of 33-77 % in area under the curve (AUC) and 65-104 % in C max. A much smaller increase was seen in edoxaban concentration at 24 h post-dose (C 24, -24 to 38 %), due to decreased V 2 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 2, resulting in an increase of 32 % in AUC and 66 % in C 24. Creatinine clearance was a significant covariate on renal clearance, whereas age and body weight significantly affected nonrenal clearance. Model-predicted steady state C min 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 min 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.

journal_name

Eur J Clin Pharmacol

authors

Yin OQ,Tetsuya K,Miller R

doi

10.1007/s00228-014-1736-4

subject

Has Abstract

pub_date

2014-11-01 00:00:00

pages

1339-51

issue

11

eissn

0031-6970

issn

1432-1041

journal_volume

70

pub_type

杂志文章,随机对照试验
  • Is the administration of doxycycline still indicated in bacterial infections of the gallbladder and the bile ducts?

    abstract::The levels of doxycycline in serum, bile and the gallbladder wall were determined in 25 patients during cholecystectomy, by means of bioassay after previous intravenous administration of doxycycline. The mean biliary level exceeded 20 microgram/ml, and the mean level in the gallbladder wall was greater than 2 microgra...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00554664

    authors: Moorthi K,Wiederholt K

    更新日期:1981-01-01 00:00:00

  • Magnesium depletion in patients on long-term chlorthalidone therapy for essential hypertension.

    abstract::Sixty patients were treated for 1 year for essential uncomplicated hypertension, 30 with beta-blockers alone (BB) and 30 with BB and chlorthalidone (CTD). BB did not affect serum K+ or Mg++. In the BB-group there was a statistically significant trend towards retention of Mg++ in a loading test, but the effect was clin...

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/BF00543964

    authors: Cocco G,Iselin HU,Strozzi C,Cesana B,Baumeler HR

    更新日期:1987-01-01 00:00:00

  • Distribution and metabolism of N(G)-nitro-L-arginine methyl ester in patients with septic shock.

    abstract:OBJECTIVE:The pharmacokinetics of N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide (NO) synthesis, was investigated in patients with septic shock. METHODS:Blood was sampled at intervals before, during and after 12-h infusion of L-NAME 1 mg x kg(-1) x h(-1) in nine septic shock patients for det...

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1007/s002280050525

    authors: Avontuur JA,Buijk SL,Bruining HA

    更新日期:1998-10-01 00:00:00

  • Association between statin-induced creatine kinase elevation and genetic polymorphisms in SLCO1B1, ABCB1 and ABCG2.

    abstract:PURPOSE:Treatment with statins requires close monitoring of serum creatine kinase (CK) levels to prevent myopathy, a common and potentially serious dose-dependent adverse effect of these drugs. We have investigated the correlation between elevated CK levels and polymorphisms in the genes encoding transporters involved ...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-014-1661-6

    authors: Ferrari M,Guasti L,Maresca A,Mirabile M,Contini S,Grandi AM,Marino F,Cosentino M

    更新日期:2014-05-01 00:00:00

  • Disposition and pharmacodynamics of diuretics and antihypertensive agents in renal disease.

    abstract::The pharmacodynamic actions and disposition of diuretic and antihypertensive agents may be significantly modified in subjects with renal disease. Most studies on this question have dealt with alterations in the elimination kinetics of these drugs and, while they generate descriptive data, minimal insight about change...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00561487

    authors: Mirkin BL,Green TP,O'Dea RF

    更新日期:1980-07-01 00:00:00

  • Ambulatory blood pressure monitoring during sustained treatment with conventional and extended-release felodipine in mild-to-moderate hypertension.

    abstract::To assess the duration of the antihypertensive effect of the dihydropiridine calcium antagonist felodipine in conventional (C-F) and slow-release (ER-F) formulations, 12 patients with essential hypertension underwent ambulatory blood pressure monitoring (ABPM) at the end of a 2-week treatment period with C-F 5 mg b.d....

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/BF00562543

    authors: Porcellati C,Verdecchia P,Gatteschi C,Benemio G,Guerrieri M,Boldrini F,Pollavini G

    更新日期:1989-01-01 00:00:00

  • Relationship between plasma concentrations and pharmacological effects of labetalol.

    abstract::In healthy normal subjects following the administration of labetalol the pharmacological effects were measured and compared with the plasma concentrations achieved. The inhibition of exercise induced tachycardia and inhibition of exercise induced increases in systolic pressure were significantly related to the adminis...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00562897

    authors: Richards DA,Maconochie JG,Bland RE,Hopkins R,Woodings EP,Martin LE

    更新日期:1977-01-03 00:00:00

  • Pharmacokinetic and pharmacodynamic interaction of single doses of valsartan and atenolol.

    abstract:OBJECTIVE:Valsartan (V), a specific inhibitor of the angiotensin II receptor subtype, AT1, has been developed for treatment of hypertension. Combination therapy with a beta-adrenoceptor blocking agent might be considered in cases with insufficient efficacy of V alone. Therefore, an interaction trial was performed to ev...

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/s002280050318

    authors: Czendlik CH,Sioufi A,Preiswerk G,Howald H

    更新日期:1997-01-01 00:00:00

  • Methodology for a multinational case-population study on liver toxicity risks with NSAIDs: the Study of Acute Liver Transplant (SALT).

    abstract:PURPOSE:The European Committee for Human Medicinal Products (CHMP) requested a multinational study with the aim to investigate the risk of acute liver failure (ALF) leading to registration for transplantation in patients exposed to non-steroidal anti-inflammatory drugs (NSAIDs). The method of this multinational, multic...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章,多中心研究

    doi:10.1007/s00228-012-1357-8

    authors: Gulmez SE,Larrey D,Pageaux GP,Lignot-Maleyran S,de Vries C,Sturkenboom M,Perez-Gutthann S,Bénichou J,Bissoli F,Horsmans Y,Bernuau J,Stricker B,Thorburn D,Blin P,Moore N

    更新日期:2013-03-01 00:00:00

  • Persistence and treatment-free interval in patients being prescribed biological drugs in rheumatology practices in Germany.

    abstract:AIMS:The goal of this study was to analyze persistence and the treatment-free interval in patients being prescribed biological drugs in rheumatology practices in Germany. METHODS:Patients who received a first prescription of biological drugs between 2008 and 2016 in 21 rheumatologists in Germany were included in this ...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-019-02627-y

    authors: Kostev K,Jacob L

    更新日期:2019-05-01 00:00:00

  • Factors associated with antithrombotic treatment decisions for stroke prevention in atrial fibrillation in the Stockholm region after the introduction of NOACs.

    abstract:PURPOSE:The purpose of this study was to investigate the influence of patient characteristics such as age and stroke and bleeding risks on decisions for antithrombotic treatment in patients with atrial fibrillation (AF). METHODS:This was a retrospective, population-based study including AF patients initiated with eith...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-017-2289-0

    authors: Komen J,Forslund T,Hjemdahl P,Wettermark B

    更新日期:2017-10-01 00:00:00

  • Effects of the Chinese herbal formula "Zuojin Pill" on the pharmacokinetics of dextromethorphan in healthy Chinese volunteers with CYP2D6*10 genotype.

    abstract:OBJECTIVE:Zuojin Pill has been shown to inhibit the cytochrome P450 (CYP) 2D6 isoenzyme in vitro. In Chinese individuals, CYP 2D6*10 is the most common allele with reduced enzyme activity. In this study, we investigated the pharmacokinetic interaction between Zuojin Pill and the sensitive CYP2D6 probe dextromethorphan ...

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1007/s00228-016-2048-7

    authors: Qiu F,Liu S,Miao P,Zeng J,Zhu L,Zhao T,Ye Y,Jiang J

    更新日期:2016-06-01 00:00:00

  • Application of a radioreceptor assay in a pharmacokinetic study of oxitropium bromide in healthy volunteers after single i.v., oral and inhalation doses.

    abstract::Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the 14C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competitio...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00558132

    authors: Ensing K,de Zeeuw RA,in 't Hout WG,Cornelissen PJ

    更新日期:1989-01-01 00:00:00

  • Binding of teicoplanin to human serum albumin.

    abstract::The interaction between the main components of the new glycopeptide antibiotic teicoplanin, A2-2, A2-3, A2-4, A2-5 and A3-1, and human serum albumin has been studied in vitro by equilibrium dialysis (pH 7.4, 37 degrees C). From Scatchard analysis of the data, the calculated association constants (Ka) were: A2-2, 2.47 ...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00544566

    authors: Assandri A,Bernareggi A

    更新日期:1987-01-01 00:00:00

  • Education on prescribing for older patients in the Netherlands: a curriculum mapping.

    abstract:PURPOSE:Pharmacology and pharmacotherapy education is being increasingly integrated in medical curricula, which might lead to a specific loss of knowledge in these subjects. This, in turn, could lead to harmful prescribing errors, especially in vulnerable older patients. METHODS:Teachers who coordinated education in D...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-015-1830-2

    authors: Keijsers CJ,de Wit JE,Tichelaar J,Brouwers JR,de Wildt DJ,de Vries PG,Jansen PA

    更新日期:2015-05-01 00:00:00

  • Population pharmacokinetics of PEGylated liposomal CPT-11 (IHL-305) in patients with advanced solid tumors.

    abstract:PURPOSE:To investigate pharmacokinetics (PK) of encapsulated CPT-11, released CPT-11 and the active metabolite SN-38 following administration of IHL-305 and to identify factors that may influence IHL-305 PK. METHODS:Plasma samples from 39 patients with solid tumors were collected in a phase I study. IHL-305 was admini...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-013-1580-y

    authors: Wu H,Infante JR,Keedy VL,Jones SF,Chan E,Bendell JC,Lee W,Zamboni BA,Ikeda S,Kodaira H,Rothenberg ML,Burris HA 3rd,Zamboni WC

    更新日期:2013-12-01 00:00:00

  • Utilisation of codeine and propoxyphene: geographic and demographic variations in prescribing, prescriber and recipient categories.

    abstract:OBJECTIVES:To assess (1) whether the utilisation of codeine or propoxyphene differs among the three major Swedish cities (Stockholm, Göteborg and Malmö) and between urban and semirural areas; (2) if so, whether it co-varies with the utilisation of other potentially dependence-promoting drugs, benzodiazepines; (3) what ...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s002280050680

    authors: Henricson K,Carlsten A,Ranstam J,Rametsteiner G,Stenberg P,Wessling A,Melander A

    更新日期:1999-10-01 00:00:00

  • Long-term nicotine substitution after application of a 16-hour nicotine patch in smoking cessation.

    abstract::The purpose of the study was to examine long-term nicotine substitution and its variability during use of a nicotine patch. In two smoking cessation studies a 16-h nicotine patch, releasing 15 mg nicotine, was applied daily for 16 h over 12 weeks, to 167 smokers. Salivary cotinine was highly correlated with plasma cot...

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/BF02280755

    authors: Nørregaard J,Tønnesen P,Simonsen K,Säwe U

    更新日期:1992-01-01 00:00:00

  • Effect of active metabolites of chlordiazepoxide and diazepam, alone or in combination with alcohol, on psychomotor skills related to driving.

    abstract::Interaction of the main metabolites of diazepam and chlordiazepoxide with alcohol was measured in two subacute double-blind cross-over experiments on 40 healthy, young volunteers. The drugs were administered for two week periods. The variables measured were choice reaction time and accuracy, eye-hand co-ordination, di...

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章

    doi:10.1007/BF00644607

    authors: Palva ES,Linnoila M

    更新日期:1978-07-30 00:00:00

  • Arginase II polymorphisms modify the hypotensive responses to propofol by affecting nitric oxide bioavailability.

    abstract:PURPOSE:Propofol anesthesia is usually accompanied by hypotensive responses, which are at least in part mediated by nitric oxide (NO). Arginase I (ARG1) and arginase II (ARG2) compete with NO synthases for their common substrate L-arginine, therefore influencing the NO formation. We examined here whether ARG1 and ARG2 ...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-020-03059-9

    authors: Oliveira-Paula GH,Coeli-Lacchini FB,Ferezin LP,Ferreira GC,Pinheiro LC,Paula-Garcia WN,Garcia LV,Tanus-Santos JE,Lacchini R

    更新日期:2021-01-07 00:00:00

  • Effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on tamoxifen metabolism.

    abstract:BACKGROUND:Tamoxifen is one of the cornerstones of endocrine therapy for breast cancer. Recently, the decreased activity CYP3A4*22 allele and the loss of function CYP3A5*3 allele have been described as potential factors that could help to explain the inter-patient variability in tamoxifen metabolism. The aim of this st...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-017-2323-2

    authors: Sanchez Spitman AB,Moes DJAR,Gelderblom H,Dezentje VO,Swen JJ,Guchelaar HJ

    更新日期:2017-12-01 00:00:00

  • Allele and genotype frequencies of polymorphic DCP1, CETP, ADRB2, and HTR2A in the Egyptian population.

    abstract:OBJECTIVE:The goal of this study was to determine the frequencies of important allelic variants of two drug targets, dipeptidyl carboxypeptidase ( DCP1) and cholesteryl ester transfer protein ( CETP), and two other drug receptors, beta-2 adrenergic receptor ( ADRB2) and 5-hydroxy tryptamine 2A receptor ( HTR2A), in the...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-002-0423-z

    authors: Hamdy SI,Hiratsuka M,Narahara K,El-Enany M,Moursi N,Ahmed MS,Mizugaki M

    更新日期:2002-04-01 00:00:00

  • Adherence to hospital drug formularies and cost of drugs in hospitals in Denmark.

    abstract:PURPOSE:To investigate adherence rates to hospital drug formularies (HDFs) and cost of drugs in hospitals. METHODS:Data on drugs used during 2010 were analyzed for ten hospitals (two hospitals from each of the five regions), constituting 30 % of hospitals and 45 % of hospital beds in Denmark. Drug use data from indivi...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-013-1540-6

    authors: Plet HT,Hallas J,Kjeldsen LJ

    更新日期:2013-10-01 00:00:00

  • Drug binding in the undernourished: a study of the binding of propranolol to alpha 1-acid glycoprotein.

    abstract::The binding of propranolol, a drug commonly used in cardiovascular disorders, to alpha 1-acid glycoprotein (AGP) was studied in vitro in malnutrition. Compared to normal and hospital controls, the level of AGP was found to be elevated in undernourished subjects with and without infection. In the same patients the free...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/BF00547044

    authors: Jagadeesan V,Krishnaswamy K

    更新日期:1985-01-01 00:00:00

  • The influence of ascites on the pharmacokinetics of piretanide in cirrhotic patients.

    abstract::The pharmacokinetics of piretanide, a new loop diuretic, were studied in seven patients with severe liver disease before and after resolution of ascites. The time to maximum concentration was significantly prolonged by the presence of ascites. Tmax after relief of ascites was similar to that seen for normal volunteers...

    journal_title:European journal of clinical pharmacology

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1007/BF00544070

    authors: Shepherd AN,Bouchier IA

    更新日期:1985-01-01 00:00:00

  • Effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects.

    abstract:OBJECTIVE:To evaluate the effect of the CYP2D6 genotype on the pharmacokinetics of tropisetron in healthy Korean subjects. METHODS:A single 5-mg capsule of tropisetron was administered orally to 13 healthy subjects. Plasma concentrations were determined by validated HPLC procedures and data were analyzed by using nonc...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-003-0595-1

    authors: Kim MK,Cho JY,Lim HS,Hong KS,Chung JY,Bae KS,Oh DS,Shin SG,Lee SH,Lee DH,Min B,Jang IJ

    更新日期:2003-06-01 00:00:00

  • The use of melatonin in Swedish children and adolescents--a register-based study according to age, gender, and medication of ADHD.

    abstract:PURPOSE:The use of melatonin is increasing among Swedish children and adolescents despite deficient knowledge of usage in these groups. The aim of this study was to investigate the use of melatonin in Swedish children and adolescents according to age, gender, dosage, treatment duration, and use of attention deficit hyp...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-015-1866-3

    authors: Furster C,Hallerbäck MU

    更新日期:2015-07-01 00:00:00

  • Hepatic CYP2A6 levels and nicotine metabolism: impact of genetic, physiological, environmental, and epigenetic factors.

    abstract:PURPOSE:We investigated the role of genetic, physiological, environmental, and epigenetic factors in regulating CYP2A6 expression and nicotine metabolism. METHODS:Human livers (n = 67) were genotyped for CYP2A6 alleles and assessed for nicotine metabolism and CYP2A6 expression (mRNA and protein). In addition, a subset...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-009-0762-0

    authors: Al Koudsi N,Hoffmann EB,Assadzadeh A,Tyndale RF

    更新日期:2010-03-01 00:00:00

  • The potential of cytokines as safety biomarkers for drug-induced liver injury.

    abstract::Drug-induced liver injury (DILI) is an event that has a detrimental impact on drug development and patient safety; therefore the identification of novel biomarkers that are both sensitive and specific to the liver would have great benefit. Inflammation is known to be associated with human cases of DILI, and given the ...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章,评审

    doi:10.1007/s00228-010-0862-x

    authors: Laverty HG,Antoine DJ,Benson C,Chaponda M,Williams D,Kevin Park B

    更新日期:2010-10-01 00:00:00

  • Theophylline treatment may adversely affect the anoxia-induced erythropoietic response without suppressing erythropoietin production.

    abstract:OBJECTIVE:To investigate the influence of theophylline on erythropoiesis in chronic obstructive pulmonary disease (COPD) and explore the potential underlying mechanisms. METHODS:We evaluated the haematological parameters and erythropoietin (EPO) values in 38 COPD patients, 18 of which had been treated with theophyllin...

    journal_title:European journal of clinical pharmacology

    pub_type: 杂志文章

    doi:10.1007/s00228-003-0640-0

    authors: Tsantes AE,Tassiopoulos ST,Papadhimitriou SI,Bonovas S,Poulakis N,Vlachou A,Filioussi K,Loukopoulos D

    更新日期:2003-09-01 00:00:00