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

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.

Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects

“…Decreased clearance of anticancer drugs in cancer patients has been reported previously. [46][47][48] In our previous study, 8 In conclusion, our data begin to address key gaps in knowledge about human protein abundance in cancer. DMEs were significantly downregulated and transporters were perturbed in CRLM.…”

“…The compound files were available in Simcyp library (Table S5), and PBPK simulations used system parameters available on the simulator for healthy and cancer populations. The effects of abundance changes (based on TPA) in CRLM were assessed using previously described models 8 : Model 1 (Healthy): default microsomal protein per gram of liver (MPPGL) and abundance levels for the healthy population (Simcyp). Model 2 (Cancer‐D): default MPPGL and abundance for the cancer population (Simcyp). Model 3 (New Cancer‐ALN): MPPGL of histologically normal tissue 8 and abundances of DMEs and transporters in histologically normal relative to healthy tissue were used for the cancer population, assuming the whole liver is histologically normal (maximum metabolic capacity). Model 4 (New Cancer‐ALC): MPPGL of cancerous tissue 8 and abundance of DMEs and transporters in tumour relative to healthy tissue were used for the cancer population, assuming the whole liver is cancerous (minimum metabolic capacity) and liver mass is unchangeable. …”

“…Liver tissue samples were fractionated to microsomes, 8 as described in Supplementary Methods. Pooled samples were made up by combining equal volumes of individual microsomes from either 15 healthy samples (HP), 16 histologically normal samples (NP) from CRLM patients or 16 matched cancerous liver samples (TP) from the same CRLM patients.…”

“…chemotherapy) are available 3 . Because liver metastasis is common, pharmacokinetics (PK) of many drugs differ in CRC patients due to perturbed system parameters 4–8 . Despite the fact that a constant dosage is often used throughout the cancer chemotherapy, there are temporal changes in pharmacodynamic (PD) targets with disease progression or remission.…”

“… 3 Because liver metastasis is common, pharmacokinetics (PK) of many drugs differ in CRC patients due to perturbed system parameters. 4 , 5 , 6 , 7 , 8 Despite the fact that a constant dosage is often used throughout the cancer chemotherapy, there are temporal changes in pharmacodynamic (PD) targets with disease progression or remission. The proteomic nature of these changes has not been well studied with respect to altered expression of drug targets during cancer progression, 9 which has been reported across different cancer types.…”