A quantitative systems pharmacology approach, incorporating a novel liver model, for predicting pharmacokinetic drug-drug interactions

PLoS One. 2017 Sep 14;12(9):e0183794. doi: 10.1371/journal.pone.0183794. eCollection 2017.

Abstract

All pharmaceutical companies are required to assess pharmacokinetic drug-drug interactions (DDIs) of new chemical entities (NCEs) and mathematical prediction helps to select the best NCE candidate with regard to adverse effects resulting from a DDI before any costly clinical studies. Most current models assume that the liver is a homogeneous organ where the majority of the metabolism occurs. However, the circulatory system of the liver has a complex hierarchical geometry which distributes xenobiotics throughout the organ. Nevertheless, the lobule (liver unit), located at the end of each branch, is composed of many sinusoids where the blood flow can vary and therefore creates heterogeneity (e.g. drug concentration, enzyme level). A liver model was constructed by describing the geometry of a lobule, where the blood velocity increases toward the central vein, and by modeling the exchange mechanisms between the blood and hepatocytes. Moreover, the three major DDI mechanisms of metabolic enzymes; competitive inhibition, mechanism based inhibition and induction, were accounted for with an undefined number of drugs and/or enzymes. The liver model was incorporated into a physiological-based pharmacokinetic (PBPK) model and simulations produced, that in turn were compared to ten clinical results. The liver model generated a hierarchy of 5 sinusoidal levels and estimated a blood volume of 283 mL and a cell density of 193 × 106 cells/g in the liver. The overall PBPK model predicted the pharmacokinetics of midazolam and the magnitude of the clinical DDI with perpetrator drug(s) including spatial and temporal enzyme levels changes. The model presented herein may reduce costs and the use of laboratory animals and give the opportunity to explore different clinical scenarios, which reduce the risk of adverse events, prior to costly human clinical studies.

MeSH terms

  • Animals
  • Drug Interactions
  • Humans
  • Liver / blood supply
  • Liver / enzymology*
  • Midazolam / pharmacokinetics*
  • Midazolam / pharmacology
  • Models, Biological

Substances

  • Midazolam

Grant support

The funder, Vertex Pharmaceutical, provided support in the form of PhD sponsoring for MHCR and welcomed MHCR in their offices for 6 months to conduct his experiments, where PL was supervising him. Furthermore, PL was attending in a regular basis meetings at the University of Nottingham from the conceptualization to the validation of the PhD. Finally he was also part of the review of this manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.