Hepatic Scaling Factors for In Vitro-In Vivo Extrapolation (IVIVE) of Metabolic Drug Clearance in Patients with Colorectal Cancer with Liver Metastasis

Research output: Contribution to journalArticlepeer-review

  • External authors:
  • Areti Maria Vasilogianni
  • Sheila Annie Peters

Abstract

In vitro-in vivo extrapolation (IVIVE) linked with physiologically based pharmacokinetic (PBPK) modelling is used to predict the fates of drugs in patients. Ideally, the IVIVE-PBPK models should incorporate “systems” information accounting for characteristics of the specific target population. There is a paucity of such scaling factors in cancer, particularly microsomal protein per gram of liver (MPPGL) and cytosolic protein per gram of liver (CPPGL). In this study, cancerous and histologically normal liver tissue from 16 patients with colorectal liver metastasis (CRLM) were fractionated to microsomes and cytosol. Protein content was measured in homogenates, microsomes and cytosol. The loss of microsomal protein during fractionation was accounted for using corrections based on NADPH cytochrome P450 reductase activity in different matrices. MPPGL was significantly lower in cancerous tissue (24.8 ± 9.8 mg/g) than histologically normal tissue (39.0 ± 13.8 mg/g). CPPGL in cancerous tissue was 42.1 ± 12.9 mg/g compared with 56.2 ± 16.9 mg/g in normal tissue. No correlations between demographics (sex, age and BMI) and MPPGL or CPPGL were apparent in the data. The generated scaling factors together with assumptions regarding the relative volumes of cancerous versus non-cancerous tissue were used to simulate plasma exposure of drugs with different extraction ratios. The PBPK simulations revealed a substantial difference in drug exposure (AUC), up to 3.3-fold, when using typical scaling factors (healthy population) instead of disease-related parameters in cancer population. These indicate the importance of using population-specific scalars in IVIVE-PBPK for different disease states.

Bibliographical metadata

Original languageEnglish
JournalDrug Metabolism and Disposition
Publication statusAccepted/In press - 2 Apr 2021