loading page

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis
  • Véronique de Bruijn,
  • Ivonne Rietjens,
  • Hans Bouwmeester
Véronique de Bruijn
Wageningen University & Research

Corresponding Author:[email protected]

Author Profile
Ivonne Rietjens
Wageningen University & Research
Author Profile
Hans Bouwmeester
Wageningen University & Research
Author Profile

Abstract

Background and Purpose – Bile acids (BA) fulfill a wide range of physiological functions, but are also involved in pathologies, such as cholestasis. Cholestasis is characterized by an intrahepatic accumulation of BAs and subsequent spillage to the systemic circulation. The aim of the present study was to develop a physiologically based pharmacokinetic (PBPK) model, that would provide a tool to predict dose-dependent BA accumulation in humans upon treatment with a Bile Salt Export Pump (BSEP) inhibitor. Experimental Approach – We developed a PBPK model describing the bile acid homeostasis using glycochenodeoxycholic acid as an exemplary BA. We compared interindividual differences by scaling the total amount of bile acids with an empirical scaling factor and alternatively by sampling randomly from a distribution describing the BSEP abundances using Markov Chain Monte Carlo simulations. Next, the effects of the BSEP-inhibitor bosentan on the bile acid levels were simulated. Key Results – The developed model adequately predicted the in vivo BA dynamics. An empirical scaling factor of 0.5 or 1.5 could readily describe the variations within and between data in human volunteers. Bosentan treatment disproportionally increased the maximum BA concentration in individuals with a large total BA pool or low BSEP abundance. Conclusion and Implications - Especially a large total BA pool size and a low BSEP abundance were predicted to be risk factors for rapid saturation of BSEP and subsequent intrahepatic BA accumulation. This model provides a first estimate of safe therapeutic external dose levels of compounds with BSEP-inhibitory properties.