Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of apixaban in healthy Japanese male subjects

Yamahira, Naomi; Frost, Charles; Fukase, Hiroyuki; Zhang, Yu; Wang, Jessie; Pursley, Janice; LaCreta, Frank; Hiraoka, Masaki

doi:10.5414/cp201967

Cited by 28 publications

(38 citation statements)

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“…Our data are overall in line with previous reports from healthy volunteers [18,20] and ACS patients [13]. According to the manufacturer, median trough values were 79 ng/mL (34 -162, 5th -95th percentile) and 103 ng/mL (41 -230, 5th -95th percentile) for patients treated with 2.5 and 5 mg BID, respectively [8].…”

Section: Discussionsupporting

confidence: 91%

“…The monitoring of apixaban anticoagulant activity has also been published and have in general shown to correlate well with apixaban plasma concentrations, however different anti-FXa assays show variable results [12 -19]. Importantly, these studies were conducted in vitro, using spiked samples [16,17,19], in healthy volunteers [15,18] or in patients with acute coronary syndrome [13,14] or venous thromboembolism [12].…”

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation

Skeppholm

Al-Aieshy

Berndtsson

et al. 2015

Thrombosis Research

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 97%

Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation

Skeppholm

Al-Aieshy

Berndtsson

et al. 2015

Thrombosis Research

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“…4, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 This analysis utilized a two‐stage approach so the majority of PK model development could be performed with data from the phase I and phase II studies (stage 1). Once data from the phase III study became available, the stage 1 models were re‐estimated (updated stage 1) and then redefined with additional covariate testing (stage 2).…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

Cirincione

Kowalski²,

Nielsen³

et al. 2018

CPT Pharmacom & Syst Pharma

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This analysis describes the population pharmacokinetics (PPK) of apixaban in nonvalvular atrial fibrillation (NVAF) subjects, and quantifies the impact of intrinsic and extrinsic factors on exposure. The PPK model was developed using data from phase I–III studies. Apixaban exposure was characterized by a two‐compartment PPK model with first‐order absorption and elimination. Predictive covariates on apparent clearance included age, sex, Asian race, renal function, and concomitant strong/moderate cytochrome P450 (CYP)3A4/P‐glycoprotein (P‐gp) inhibitors. Individual covariate effects generally resulted in < 25% change in apixaban exposure vs. the reference NVAF subject (non‐Asian, male, aged 65 years, weighing 70 kg without concomitant CYP3A4/P‐gp inhibitors), except for severe renal impairment, which resulted in 55% higher exposure than the reference subject. The dose‐reduction algorithm resulted in a ~27% lower median exposure, with a large overlap between the 2.5‐mg and 5‐mg groups. The impact of Asian race on apixaban exposure was < 15% and not considered clinically significant.

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“…The apixaban pharmacokinetic profile observed in this study is consistent with previous reports, including the extent of variability that is considered low to moderate. The conduct‐related concerns the professors raised were not factors in the study.…”

mentioning

confidence: 73%

Response to Letter to the Editor From Drs. Stöllberger and Finsterer

Frost

Chang

Zhang

et al. 2016

The Journal of Clinical Pharma

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Dear Editor,We appreciate Professors Stöllberger's and Finsterer's interest and the opportunity to address their questions, which mainly concerned potential sources of variability in our apixaban renal impairment study. 1 The apixaban pharmacokinetic profile observed in this study is consistent with previous reports, 2-5 including the extent of variability that is considered low to moderate. The conduct-related concerns the professors raised were not factors in the study. This was a wellcontrolled and carefully designed study conducted in accordance with international guidelines at highly qualified and trained sites. All subjects consumed the correct dose, as confirmed by mouth-check, after a 10-hour fast and consumed standardized meals at specified times following administration. Concomitant medications and foods known to modulate CYP3A or P-gp activity were prohibited prior to and during participation. When appropriate, other comedications were held 4 hours before and after apixaban administration. Smoking is not expected to impact apixaban pharmacokinetics; in any case, the use of tobacco-related products was prohibited for 2 hours prior to and 6 hours after apixaban administration.Renal impairment is a complex disorder with diversity in etiology, severity, and rate of progression as well as comorbidities. Our study was not designed to evaluate the effects of individual chronic kidney disease characteristics; rather, it evaluated the relationship between an overall measure of renal function and apixaban pharmacokinetics, as is common practice. 6 Our study included individuals with stable chronic renal impairment, and the majority, 20 of 24 subjects, had underlying hypertension and/or diabetes. Conditions including hypercholesterolemia, anemia, and reflux were present in some individuals. Subjects with a history of drug abuse were excluded from the study. There was no evidence of hepatic impairment in baseline examinations or laboratory results. Regardless of medical history or comorbidities, the renal function assessments in an individual subject were highly consistent across the 4 methods used to determine renal function in our study. We are encouraged by the consistency between these results and those in subjects with end-stage renal disease. 7 Therefore, we remain confident that the effect of chronic renal impairment on apixaban pharmacokinetics was well characterized.Apixaban pharmacokinetics are linear over the therapeutic dose range and do not exhibit any time dependencies. 3,4 Therefore, the effect of renal impairment on single-dose apixaban pharmacokinetics is predictive of what would be expected at steady-state and reflects the relative increase in apixaban exposure resulting from accumulation following multiple dosing in renally impaired patients.Our study was not designed to determine the safety and efficacy of apixaban in atrial fibrillation patients with renal impairment. We discussed available clinical data for atrial fibrillation in our manuscript, 8,9 which are included in the meta-analysis 10 ...

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Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of apixaban in healthy Japanese male subjects

Cited by 28 publications

References 0 publications

Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation

Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

Response to Letter to the Editor From Drs. Stöllberger and Finsterer

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