Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects

Abstract

AIMApixaban is an oral, direct, factor-Xa inhibitor approved for thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. This open label, parallel group study investigated effects of extremes of body weight on apixaban pharmacokinetics, pharmacodynamics, safety and tolerability. METHODFifty-four healthy subjects were enrolled [18 each into low (Յ50 kg), reference (65-85 kg) and high (Ն120 kg) body weight groups]. Following administration of a single oral dose of 10 mg apixaban, plasma and urine samples were collected for determination of apixaban pharmacokinetics and anti-factor Xa activity. Adverse events, vital signs and laboratory assessments were monitored. RESULTSCompared with the reference body weight group, low body weight had approximately 27% [90% confidence interval (CI): 8-51%] and 20% (90% CI: 11-42%) higher apixaban maximum observed plasma concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUC(0,•)), respectively, and high body weight had approximately 31% (90% CI: 18-41%) and 23% (90% CI: 9-35%) lower apixaban Cmax and AUC(0,•), respectively. Apixaban renal clearance was similar across the weight groups. Plasma anti-factor Xa activity showed a direct, linear relationship with apixaban plasma concentration, regardless of body weight group. Apixaban was well tolerated in this study. CONCLUSIONThe modest change in apixaban exposure is unlikely to require dose adjustment for apixaban based on body weight alone. However, caution is warranted in the presence of additional factors (such as severe renal impairment) that could increase apixaban exposure.

Population Pharmacokinetics of Apixaban in Subjects With Nonvalvular Atrial Fibrillation

“…The model allowed for empirical separation of the total plasma CL/F into renal and nonrenal components with predicted increases in AUC ss of 9%, 28%, and 55% for patients with NVAF with mild (cCrCL = 65 mL/minute), moderate (40 mL/minute), and severe (15 mL/minute) renal impairment, respectively, compared with those with normal renal function. The results are generally consistent with the estimates from phase I studies20, 22 in which mild, moderate, and severe renal impairment were associated with an ~16%, 29%, and 44% higher estimated apixaban AUC INF than those with normal renal funtion 20. Several factors identified in previous phase I clinical trials, including age, sex, body weight, and mild‐to‐moderate renal impairment, were shown to modestly influence apixaban PK and these factors alone do not require any clinical dose adjustment.…”

“…Individually, these factors have been shown to have limited effects on exposure,20, 21, 22 both within the analyses described herein as well as in individual trials. In addition, each of these factors on their own was not expected to result in clinically meaningful change in the benefit–risk profile of apixaban, as confirmed by a subgroup analysis performed in subjects who met only one of the dose‐reduction criteria 37.…”

“…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).…”

Peak plasma concentration of direct oral anticoagulants in obese patients weighing over 120 kilograms: A retrospective study

“…A subgroup analysis of the ARISTOTLE trial based on BW reported that higher BW and BMI were associated with lower all‐cause mortality rate and lower risk of stroke or systemic embolism 22. A pharmacokinetic study of healthy volunteers taking rivaroxaban reported that the area under the curve (AUC) was unaffected by BW,23 the volume of distribution was moderately influenced by BW in patients taking rivaroxaban,24 and a mean increase in BW of 83% resulted in a limited 23% decrease of the AUC in healthy volunteers taking apixaban 25. A large prospective study of real‐life patients receiving DOACs for treatment of atrial fibrillation or VTE, which included 98 patients with BMI >40 kg/m 2 , did not find any indication that high BMI is associated with reduced DOAC efficacy or safety 26.…”

Determination of Apixaban Levels in Human Plasma by a High-Throughput Liquid Chromatographic Tandem Mass Spectrometry Assay / Determinarea rapidă a apixabanului în plasma umană prin cromatografie de lichide de înaltă performanță cuplată cu spectrometrie de masă în tandem

“…A few studies of metabolism and/or pharmacokinetics briefly presents the LC-MS/MS methods applied to determine apixaban plasma lev- [25], and Wang et al [26] determined pharmacokinetics of apixaban in healthy subjects using a LC-MS/MS method validated by Intertek Pharmaceutical Services with a LLOQ of 1 ng/mL. Frost et al studied pharmacokinetics of apixaban after single dose in healthy subjects by a LC-MS/MS method with LLOQ of 1 ng/mL and quantification range of 1 -1000 ng/mL [7].…”