Pharmacokinetics, pharmacodynamics, and safety of apixaban in subjects with end‐stage renal disease on hemodialysis

Abstract

An open-label, parallel-group, single-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, and safety of apixaban in 8 subjects with end-stage renal disease (ESRD) on hemodialysis compared with 8 subjects with normal renal function. A single oral 5-mg dose of apixaban was administered once to healthy subjects and twice to subjects with ESRD, separated by ≥7 days: 2 hours before (on hemodialysis) and immediately after a 4-hour hemodialysis session (off hemodialysis). Blood samples were collected for determination of apixaban pharmacokinetic parameters, measures of clotting (prothrombin time, international normalized ratio, activated partial thromboplastin time), and anti-factor Xa (FXa) activity. Compared with healthy subjects, apixaban Cmax and AUCinf were 10% lower and 36% higher, respectively, in subjects with ESRD off hemodialysis. Hemodialysis in subjects with ESRD was associated with reductions in apixaban Cmax and AUCinf of 13% and 14%, respectively. The percent change from baseline in clotting measures was similar in healthy subjects and subjects with ESRD, and differences in anti-FXa activity were similar to differences in apixaban concentration. A single 5-mg oral dose of apixaban was well tolerated in both groups. In conclusion, ESRD resulted in a modest increase (36%) in apixaban AUC and no increase in Cmax , and hemodialysis had a limited impact on apixaban clearance.

Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease

“…The AUC in patients with ESKD was 36% higher versus controls (49). Because of its high degree of protein binding, dialysis clearance is low (18 ml/min), resulting in a 14% decrease in drug exposure (49). In a recent retrospective analysis of patients on hemodialysis, cumulative days of apixaban use in an outpatient setting, higher total daily apixaban doses, and total hemodialysis sessions were independent risk factors for bleeding events (adjusted odds ratio, 13.07; 95% CI, 1.54 to 110.54; adjusted odds ratio, 1.72; 95% CI, 1.20 to 2.48; and adjusted odds ratio, 2.04; 95% CI, 1.06 to 3.92, respectively) (50).…”

“…After 2 hours of drug administration, a 4-hour hemodialysis session was performed with dialysate flow rate of 500 ml/min and blood flow rate of 350-500 ml/min. The AUC in patients with ESKD was 36% higher versus controls (49). Because of its high degree of protein binding, dialysis clearance is low (18 ml/min), resulting in a 14% decrease in drug exposure (49).…”

“…An open label, parallel group, single 5-mg dose PK/PD study was conducted in eight patients with ESKD and eight healthy controls (49). After 2 hours of drug administration, a 4-hour hemodialysis session was performed with dialysate flow rate of 500 ml/min and blood flow rate of 350-500 ml/min.…”

Apixaban in the Treatment of Atrial Fibrillation: Randomized Trials and Everyday Clinical Practice

“…Так, в 2016 г. бы-ли опубликованы результаты исследования фармакокинетики, фармакодинамики и безо-пасности однократного приема апиксабана в дозе 5 мг у 8 пациентов с терминальной по-чечной недостаточностью (клиренс креати-нина менее 15 мл/мин), которым на постоян-ной основе выполняется гемодиализ. Иссле-дование показало, что основные параметры фармакокинетики и фармакодинамики прин-ципиально не отличались от таковых у здоро-вых волонтеров [35]. На основании результа-тов этого исследования FDA одобрило приме-нение апиксабана в полной дозе 5 мг 2 р/сут у пациентов с терминальной почечной недо-статочностью при условии регулярного про-ведения гемодиализа (дозу следует снижать до 2,5 мг 2 р/сут у пациентов 80 лет и старше либо имеющих массу тела менее 60 кг).…”

Anticoagulation for Atrial Fibrillation in End-stage Kidney Disease

“…A single dose pharmacokinetic study of apixaban compared eight HD patients with eight controls with normal renal function and found a 36% increase in area under the curve (AUC) (51). Following this study, FDA labeling for the product changed from "no data to inform the use of patients with creatinine clearance <15mL/min or on dialysis" to a recommended dose in ESKD of 5mg twice daily or 2.5mg twice daily if the patient is aged over 80 years or body weight is less than 60kg (50).…”