Journal Article

Characterizing Apixaban Pharmacokinetics Through Physiologically‐Based Pharmacokinetic Modeling: Critical Role of Biliary Secretion and Enterohepatic Circulation in Humans

Tomi, Masatoshi, Sugiyama, Yuichi, Tsuchitani, Toshiaki, Kou, Wen

2026

Overview

Apixaban, a factor Xa inhibitor, is a direct oral anticoagulant with a well‐balanced elimination; it is eliminated evenly via feces, urine (with no active secretion), and as metabolites after oral administration. The common understanding is that biliary secretion and enterohepatic circulation (EHC) of apixaban are limited in humans, and that fecal excretion may be attributable to intestinal secretion. However, a decrease in apixaban blood concentration with activated charcoal coadministration in humans suggests possible involvement of EHC. This study aimed to evaluate the contribution of biliary excretion, EHC, and intestinal secretion to apixaban pharmacokinetics (PK) using a physiologically‐based pharmacokinetic (PBPK) model. A top‐down analysis was performed using blood concentration and mass balance data from healthy volunteers. Model parameters were optimized using the Cluster‐Gauss Newton method (CGNM), followed by the bootstrap method. The model accurately described observed data and indicated moderate to high biliary secretion relative to metabolic clearance. Simulated biliary secretion into the duodenum well predicted the biliary secretion data in humans (< 1% of dose at 8 h post‐dose). Virtual knockout of EHC resulted in a shortened half‐life from 8.7 to 2.9 h, and 17% and 55% decrease in area under the concentration curve (AUC) and fecal excretion after intravenous dosing, respectively, confirming the significant contribution of biliary excretion and EHC. The model also accurately described apixaban PK with activated charcoal coadministration at 2 or 6 h post‐dose. Although further experimental validation (e.g., sandwich‐cultured hepatocytes) would strengthen these findings, our study demonstrates that biliary secretion and EHC play a substantial role in apixaban elimination and disposition in humans. Study Highlights What is the current knowledge on the topic? ○Apixaban elimination is thought to occur through multiple pathways: fecal excretion, metabolism, and urinary excretion where its clearance can be explained by glomerular filtration. Biliary secretion and enterohepatic circulation (EHC) are considered to play minimal roles based on animal and human studies. What question did this study address? ○This study challenged the current understanding of apixaban's elimination pathway by investigating the extent of biliary secretion and EHC in humans using PBPK modeling. What does this study add to our knowledge? ○Our analysis revealed substantial biliary secretion and EHC of apixaban in humans, which did not contradict previous interpretations from short‐term bile collection studies. How might this change drug discovery, development, and/or therapeutics? ○Neither intestinal secretion in animals nor limited bile recovery in short‐term sampling in humans should be interpreted as evidence for minimal biliary elimination and EHC in humans, highlighting the importance of comprehensive modeling approaches in drug disposition studies.

• Publisher: John Wiley & Sons, Inc,Wiley
• Subject: Administration, Oral / Adult / apixaban / Bile - metabolism / Bile ducts / biliary secretion / cluster gauss‐Newton method / Confidence intervals / Drug dosages / enterohepatic circulation / Enterohepatic Circulation - physiology / Factor Xa Inhibitors - administration & dosage / Factor Xa Inhibitors - pharmacokinetics / Feces / Female / Gallbladder / Healthy Volunteers / Hepatobiliary Elimination / Humans / Male / Metabolism / Metabolites / Models, Biological / Oral administration / PBPK model / Pharmacokinetics / Plasma / Pyrazoles - administration & dosage / Pyrazoles - pharmacokinetics / Pyridones - administration & dosage / Pyridones - pharmacokinetics / Small intestine / Young Adult