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

• Published in: Drug metabolism and disposition Vol. 49; no. 7; pp. 563 - 571
• Main Authors: Vasilogianni, Areti-Maria, Achour, Brahim, Scotcher, Daniel, Peters, Sheila Annie, Al-Majdoub, Zubida M, Barber, Jill, Rostami-Hodjegan, Amin
• Format: Journal Article
• Language: English
• Published: United States 01-07-2021
• Subjects: Adult; Aged; Aged, 80 and over; Antinematodal Agents - administration & dosage; Antinematodal Agents - pharmacokinetics; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Dose-Response Relationship, Drug; Female; Hepatectomy; Hepatobiliary Elimination; Humans; Liver - metabolism; Liver - pathology; Liver - surgery; Liver Neoplasms - physiopathology; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Male; Metabolic Clearance Rate; Microsomes, Liver - metabolism; Middle Aged; Models, Biological
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.121.000359

In vitro-in vivo extrapolation (IVIVE) linked with physiologically based pharmacokinetics (PBPK) modeling 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 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 body mass index) and MPPGL or CPPGL were apparent in the data. The generated scaling factors together with assumptions regarding the relative volumes of cancerous versus noncancerous tissue were used to simulate plasma exposure of drugs with different extraction ratios. The PBPK simulations revealed a substantial difference in drug exposure (area under the curve), 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. SIGNIFICANCE STATEMENT: Accuracy in predicting the fate of drugs from in vitro data using IVIVE-PBPK depends on using correct scaling factors. The values for two of such scalars, namely microsomal and cytosolic protein per gram of liver, is not known in patients with cancer. This study presents, for the first time, scaling factors from cancerous and matched histologically normal livers. PBPK simulations of various metabolically cleared drugs demonstrate the necessity of population-specific scaling for model-informed precision dosing in oncology.