Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban

Abstract

This open-label study evaluated apixaban pharmacokinetics, pharmacodynamics, and safety in subjects with mild, moderate, or severe renal impairment and in healthy subjects following a single 10-mg oral dose. The primary analysis determined the relationship between apixaban AUC∞ and 24-hour creatinine clearance (CLcr ) as a measure of renal function. The relationships between 24-hour CLcr and iohexol clearance, estimated CLcr (Cockcroft-Gault equation), and estimated glomerular filtration rate (modification of diet in renal disease [MDRD] equation) were also assessed. Secondary objectives included assessment of safety and tolerability as well as international normalized ratio (INR) and anti-factor Xa activity as pharmacodynamic endpoints. The regression analysis showed that decreasing renal function resulted in modestly increased apixaban exposure (AUC∞ increased by 44% in severe impairment with a 24-hour CLcr of 15 mL/min, compared with subjects with normal renal function), but it did not affect Cmax or the direct relationship between apixaban plasma concentration and anti-factor Xa activity or INR. The assessment of renal function measured by iohexol clearance, Cockcroft-Gault, and MDRD was consistent with that determined by 24-hour CLcr . Apixaban was well tolerated in this study. These results suggest that dose adjustment of apixaban is not required on the basis of renal function alone.

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).…”

Evolving Treatments for Arterial and Venous Thrombosis

“…[12][13][14][15] Consequently, the DOACs can accumulate in patients with severe renal impairment, they should not be used in patients with a creatinine clearance <15 mL/min, and they should be used with caution in those with a creatinine clearance between 15 and 30 mL/min. [26][27][28][29] The distinct pharmacological properties of the DOACs endow them with potential advantages and disadvantages compared with VKAs. These are summarized in the following section.…”

Model-based meta-analysis to evaluate optimal doses of direct oral factor Xa inhibitors in atrial fibrillation patients

“…Therefore, it was possible to extend this model to apixaban and edoxaban by adjusting the slope for the treatment effect based on the prior reports. 24,25 In extending the model, the effects of differences in sensitivity of thromboplastin reagents was corrected by additionally adjusting the slope parameters in each model such that the models represent the PT values of RecombiplasTin, which was the most sensitive reagent in accordance with a method reported by Gosselin et al 26 The details for the population PK and PK/PD models used in the analysis are provided in supplemental Methods and supplemental Table 1.…”