Drug Metab Dispos. 2024 Feb 29:DMD-AR-2023-001629. doi: 10.1124/dmd.123.001629. Online ahead of print.

ABSTRACT

In vitro-in vivo extrapolation (IVIVE) allows prediction of clinical outcomes across populations from in vitro data using specific scalars tailored to the biological characteristics of each population. This study experimentally determined scalars for patients with varying degrees of non-alcoholic fatty liver disease (NAFLD), ranging from fatty liver to non-alcoholic steatohepatitis (NASH) and cirrhosis. Microsomal, S9 and cytosol fractions were extracted from 36 histologically normal and 66 NAFLD livers (27 NAFL, 13 NASH, and 26 NASH with cirrhosis). Corrected microsomal protein per gram liver (MPPGL) progressively decreased with disease severity (27.2, 28.6, 24.5 mg/g in NAFL, NASH, and NASH/cirrhosis, respectively, compared with 37.2 mg/g in normal livers; ANOVA, p < 0.001). Homogenate, S9 and cytosolic protein showed a consistent trend of decline in NASH/cirrhosis relative to normal control (post-hoc t-test, p < 0.05). No differences across the groups were observed in homogenate, S9, cytosolic and microsomal protein content in matched kidney samples. MPPGL-based scalars that combine protein content with liver size revealed that the reduction in MPPGL in NAFL and NASH was compensated by the reported increase in liver size (relative scalar ratios of 0.94 and 0.99, respectively), which was not the case with NASH/cirrhosis (ratio of 0.61), compared with healthy control. PBPK-informed Global sensitivity analysis (GSA) of the relative contribution of IVIVE scalars (hepatic CYP3A4 abundance, MPPGL, liver size) to variability in exposure (AUC) to three CYP3A substrates (alprazolam, midazolam, ibrutinib) revealed enzyme abundance as the most significant parameter, followed by MPPGL, while liver volume was the least impactful factor. Significance Statement NAFLD-specific scalars necessary for extrapolation from microsomal or cytosolic in vitro systems to liver tissue are lacking. These scalars are required in clearance prediction and dose selection in NAFL and NASH populations. Reported disease-driven changes have focused on cirrhotic livers, with no data on the initial stages of liver disease. We obtained experimental values for microsomal, cytosolic and S9 fractions and assessed the relative impact of microsomal scalars on predicted exposure to different substrate drugs using physiologically based pharmacokinetics.

PMID:38423789 | DOI:10.1124/dmd.123.001629