PMID- 33980603
OWN - NLM
STAT- MEDLINE
DCOM- 20220215
LR  - 20220215
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 49
IP  - 7
DP  - 2021 Jul
TI  - Hepatic Scaling Factors for In Vitro-In Vivo Extrapolation of Metabolic Drug 
      Clearance in Patients with Colorectal Cancer with Liver Metastasis.
PG  - 563-571
LID - 10.1124/dmd.121.000359 [doi]
AB  - 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.
CI  - Copyright (c) 2021 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Vasilogianni, Areti-Maria
AU  - Vasilogianni AM
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, 
      School of Health Sciences, University of Manchester, Manchester, United Kingdom 
      (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative 
      Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, 
      Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom 
      (A.R.-H.).
FAU - Achour, Brahim
AU  - Achour B
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, 
      School of Health Sciences, University of Manchester, Manchester, United Kingdom 
      (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative 
      Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, 
      Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom 
      (A.R.-H.).
FAU - Scotcher, Daniel
AU  - Scotcher D
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, 
      School of Health Sciences, University of Manchester, Manchester, United Kingdom 
      (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative 
      Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, 
      Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom 
      (A.R.-H.).
FAU - Peters, Sheila Annie
AU  - Peters SA
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, 
      School of Health Sciences, University of Manchester, Manchester, United Kingdom 
      (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative 
      Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, 
      Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom 
      (A.R.-H.).
FAU - Al-Majdoub, Zubida M
AU  - Al-Majdoub ZM
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, 
      School of Health Sciences, University of Manchester, Manchester, United Kingdom 
      (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative 
      Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, 
      Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom 
      (A.R.-H.).
FAU - Barber, Jill
AU  - Barber J
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, 
      School of Health Sciences, University of Manchester, Manchester, United Kingdom 
      (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative 
      Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, 
      Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom 
      (A.R.-H.).
FAU - Rostami-Hodjegan, Amin
AU  - Rostami-Hodjegan A
AD  - Centre for Applied Pharmacokinetic Research, Division of Pharmacy and Optometry, 
      School of Health Sciences, University of Manchester, Manchester, United Kingdom 
      (A.-M.V., B.A., D.S., Z.M.A.-M., J.B., A.R.-H.); Translational Quantitative 
      Pharmacology, BioPharma, R&D Global Early Development, Merck KGaA, Darmstadt, 
      Germany (S.A.P.); and Certara, Inc. (Simcyp Division), Sheffield, United Kingdom 
      (A.R.-H.) amin.rostami@manchester.ac.uk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210512
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Antinematodal Agents)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antinematodal Agents/administration & dosage/*pharmacokinetics
MH  - Colorectal Neoplasms/drug therapy/*pathology
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Hepatectomy
MH  - Hepatobiliary Elimination
MH  - Humans
MH  - Liver/*metabolism/pathology/surgery
MH  - Liver Neoplasms/*physiopathology/secondary/therapy
MH  - Male
MH  - Metabolic Clearance Rate
MH  - Microsomes, Liver/metabolism
MH  - Middle Aged
MH  - *Models, Biological
EDAT- 2021/05/14 06:00
MHDA- 2022/02/16 06:00
CRDT- 2021/05/13 05:43
PHST- 2021/01/05 00:00 [received]
PHST- 2021/04/05 00:00 [accepted]
PHST- 2021/05/14 06:00 [pubmed]
PHST- 2022/02/16 06:00 [medline]
PHST- 2021/05/13 05:43 [entrez]
AID - dmd.121.000359 [pii]
AID - 10.1124/dmd.121.000359 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2021 Jul;49(7):563-571. doi: 10.1124/dmd.121.000359. Epub 2021 
      May 12.