title: Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations.
abstract: Development of submodels of organs within physiologically-based pharmacokinetic (PBPK) principles and beyond simple perfusion limitations may be challenging because of underdeveloped in vitro-in vivo extrapolation approaches or lack of suitable clinical data for model refinement. However, advantage of such models in predicting clinical observations in divergent patient groups is now commonly acknowledged. Mechanistic understanding of altered renal secretion in renal impairment is one area that may benefit from such models, despite knowledge gaps in renal pathophysiology. In the current study, a PBPK kidney model was developed for digoxin, accounting for the roles of organic anion transporting peptide 4C1 (OATP4C1) and P-glycoprotein (P-gp) in its tubular secretion, with the aim to investigate the impact of age and renal impairment (moderate to severe) on renal drug disposition. Initial PBPK simulations based on changes in glomerular filtration rate (GFR) underestimated the observed reduction in digoxin renal excretion clearance (CLR) in subjects with moderately impaired renal function relative to healthy. Reduction in either proximal tubule cell number or the OATP4C1 abundance in the mechanistic kidney model successfully predicted 59% decrease in digoxin CLR, in particular when these changes were proportional to reduction in GFR. In contrast, predicted proximal tubule concentration of digoxin was only sensitive to changes in the transporter expression/ million proximal tubule cells. Based on the mechanistic modeling, reduced proximal tubule cellularity and OATP4C1 abundance, and inhibition of OATP4C1-mediated transport, are proposed as possible causes of reduced digoxin renal secretion in renally impaired patients.
authors.affiliation: Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom (D.S., A.G., A.R.-H.); DMPK, Oncology iMed, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, United Kingdom (C.R.J.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Scotcher
authors.affiliation: Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom (D.S., A.G., A.R.-H.); DMPK, Oncology iMed, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, United Kingdom (C.R.J.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.).
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jones
authors.affiliation: Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom (D.S., A.G., A.R.-H.); DMPK, Oncology iMed, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, United Kingdom (C.R.J.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.).
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Galetin
authors.affiliation: Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, United Kingdom (D.S., A.G., A.R.-H.); DMPK, Oncology iMed, AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, United Kingdom (C.R.J.); and Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, United Kingdom (A.R.-H.) amin.rostami@manchester.ac.uk.
authors.forename: Amin
authors.initials: A
authors.lastname: Rostami-Hodjegan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D004077:Digoxin / Q000493:pharmacokinetics*; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D027361:Organic Anion Transporters / Q000378:metabolism; D065667:Renal Elimination / Q000187:drug effects / Q000502:physiology; D051437:Renal Insufficiency / Q000378:metabolism / Q000503:physiopathology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D027361:Organic Anion Transporters; C484530:SLCO4C1 protein, human; D004077:Digoxin