Physiologically‐Based Pharmacokinetic Model of Morphine and Morphine‐3‐Glucuronide in Nonalcoholic Steatohepatitis

Abstract

Nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease, is increasing in prevalence. NASH‐related alterations in hepatic protein expression (e.g., transporters) and in overall physiology may affect drug exposure by altering drug disposition and elimination. The aim of this study was to build a physiologically‐based pharmacokinetic (PBPK) model to predict drug exposure in NASH by incorporating NASH‐related changes in hepatic transporters. Morphine and morphine‐3‐glucuronide (M3G) were used as model compounds. A PBPK model of morphine with permeability‐limited hepatic disposition was extended to include M3G disposition and enterohepatic recycling (EHR). The model captured the area under the plasma concentration‐time curve (AUC) of morphine and M3G after intravenous morphine administration within 0.82‐fold and 1.94‐fold of observed values from 3 independent clinical studies for healthy adult subjects (6, 10, and 14 individuals). When NASH‐related changes in multidrug resistance‐associated protein 2 (MRP2) and MRP3 were incorporated into the model, the predicted M3G mean AUC in NASH was 1.34‐fold higher compared to healthy subjects, which is slightly lower than the observed value (1.63‐fold). Exploratory simulations on other physiological changes occurring in NASH (e.g., moderate decreases in glomerular filtration rate and portal vein blood flow) revealed that the effect of transporter changes was most prominent. Additionally, NASH‐related transporter changes resulted in decreased morphine EHR, which could be important for drugs with extensive EHR. This study is an important first step to predict drug disposition in complex diseases such as NASH using PBPK modeling.

Development and Evaluation of a Virtual Population of Children with Obesity for Physiologically Based Pharmacokinetic Modeling

“…Some clinical studies in children with obesity infer changes in metabolic enzyme activity from drug clearance or metabolite formation rate, but these are indirect measures that can be complicated by comorbidities, duration of obesity, or concomitant drug administration. Some important clinical and in vitro studies of adult patients with nonalcoholic steatohepatitis, a common comorbidity of obesity, found substantially altered organic anion transporting polypeptide and multidrug resistance-associated protein transporter activity [39][40][41]. These changes should be considered when modeling drugs with high transport activity, especially as these transporter changes are explored in children.…”

The Role of Uptake and Efflux Transporters in the Disposition of Glucuronide and Sulfate Conjugates

“…In patients with NASH, systemic exposure to morphine-3-G, morphine-6-G and acetaminophen-G is increased ( Canet et al, 2015 ; Ferslew et al, 2015 ). This is likely due to the increased abundance of hepatic MRP3 and mislocalization of MRP2 in NASH, which results in increased efflux into the blood circulation and reduced biliary excretion ( Hardwick et al, 2011 ; Vildhede et al, 2020 ; Sjöstedt et al, 2021 ). On the other hand, an observed trend for decreasing acetaminophen sulfate levels could be due to altered sulfonation activity caused by impaired sulfur activation in NASH ( Canet et al, 2015 ), which highlights the importance (and challenge) of distinguishing changes in metabolite formation from transporter-mediated alterations.…”

Characterizing Pharmacokinetics in Children With Obesity—Physiological, Drug, Patient, and Methodological Considerations

“…There is even less evidence to inform potential changes in transporter activity in children with obesity. While some studies of adults with nonalcoholic steatohepatitis, a common obesity-related fibro-inflammatory disease of the liver, show altered transport by organic anion transporting polypeptide (OATP) and multidrug resistance-associated protein (MRP), such investigations have yet to be explored in adults or children with obesity specifically ( Pierre et al, 2017 ; Ali et al, 2018 ; Sjöstedt et al, 2021 ).…”