title: In Vitro-In Vivo Extrapolation Scaling Factors for Intestinal P-glycoprotein and Breast Cancer Resistance Protein: Part II. The Impact of Cross-Laboratory Variations of Intestinal Transporter Relative Expression Factors on Predicted Drug Disposition.
abstract: Relative expression factors (REFs) are used to scale in vitro transporter kinetic data via in vitro-in vivo extrapolation linked to physiologically based pharmacokinetic (IVIVE-PBPK) models to clinical observations. Primarily two techniques to quantify transporter protein expression are available, immunoblotting and liquid chromatography-tandem mass spectrometry. Literature-collated REFs ranged from 0.4 to 5.1 and 1.1 to 90 for intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), respectively. The impact of using human jejunum-Caco-2 REFs for P-gp (REFiP-gp) and BCRP (REFiBCRP), generated from the same samples and using different proteomic methodologies from independent laboratories, on PBPK outcomes was assessed. A 5-fold decrease in REFiP-gp for a single oral dose of digoxin resulted in a 1.19- and 1.31-fold higher plasma area under the curve and Cmax, respectively. All generated REFiP-gp values led to simulated digoxin Cmax values within observed ranges; however, combining kinetic data generated from a different laboratory with the 5-fold lower REFiP-gp could not recover a digoxin-rifampicin drug-drug interaction, emphasizing the necessity to obtain transporter-specific kinetic estimates and REFs from the same in vitro system. For a theoretical BCRP compound, with absorption taking place primarily in the jejunum, a decrease in the REFiBCRP from 2.22 (University of Manchester) to 1.11 (Bertin Pharma) promoted proximal intestinal absorption while delaying tmax 1.44-fold. Laboratory-specific differences in REF may lead to different IVIVE-PBPK outcomes. To understand the mechanisms underlying projected pharmacokinetic liabilities, it is important to assess the potential impact of bias on the generation of REFs on an interindividual basis within a target population.
authors: Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.) matthew.harwood@certara.com.
authors: Matthew D
authors: MD
authors: Harwood
authors: Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.).
authors: Brahim
authors: B
authors: Achour
authors: Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.).
authors: Sibylle
authors: S
authors: Neuhoff
authors: Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.).
authors: Matthew R
authors: MR
authors: Russell
authors: Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.).
authors: Gordon
authors: G
authors: Carlson
authors: Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.).
authors: Geoffrey
authors: G
authors: Warhurst
authors: Gut Barrier Group, Inflammation and Repair, University of Manchester, Salford Royal NHS Trust, Salford, United Kingdom (M.D.H., G.C., G.W.); Simcyp Limited (a Certara company), Blades Enterprise Centre, Sheffield, United Kingdom (M.D.H., S.N., A.R.-H.); and Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, Stopford Building, Manchester, United Kingdom (B.A., M.R.R., A.R.-H.).
authors: Amin
authors: A
authors: Rostami-Hodjegan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology*; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D004077:Digoxin / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007583:Jejunum / Q000378:metabolism*; D007700:Kinetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D040901:Proteomics / Q000379:methods
chemical_list: C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D009363:Neoplasm Proteins; D004077:Digoxin