title: Key to Opening Kidney for In Vitro-In Vivo Extrapolation Entrance in Health and Disease: Part II: Mechanistic Models and In Vitro-In Vivo Extrapolation.
abstract: It is envisaged that application of mechanistic models will improve prediction of changes in renal disposition due to drug-drug interactions, genetic polymorphism in enzymes and transporters and/or renal impairment. However, developing and validating mechanistic kidney models is challenging due to the number of processes that may occur (filtration, secretion, reabsorption and metabolism) in this complex organ. Prediction of human renal drug disposition from preclinical species may be hampered by species differences in the expression and activity of drug metabolising enzymes and transporters. A proposed solution is bottom-up prediction of pharmacokinetic parameters based on in vitro-in vivo extrapolation (IVIVE), mediated by recent advances in in vitro experimental techniques and application of relevant scaling factors. This review is a follow-up to the Part I of the report from the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25th-29th October 2015) which focuses on IVIVE and mechanistic prediction of renal drug disposition. It describes the various mechanistic kidney models that may be used to investigate renal drug disposition. Particular attention is given to efforts that have attempted to incorporate elements of IVIVE. In addition, the use of mechanistic models in prediction of renal drug-drug interactions and potential for application in determining suitable adjustment of dose in kidney disease are discussed. The need for suitable clinical pharmacokinetics data for the purposes of delineating mechanistic aspects of kidney models in various scenarios is highlighted.
authors: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Daniel
authors: D
authors: Scotcher
authors: DMPK, Oncology iMed, AstraZeneca R&D Alderley Park, Macclesfield, Cheshire, UK.
authors: Christopher
authors: C
authors: Jones
authors: Drug Disposition, Lilly Research Laboratories, Indianapolis, Indiana, 46203, USA.
authors: Maria
authors: M
authors: Posada
authors: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK.
authors: Aleksandra
authors: A
authors: Galetin
authors: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, University of Manchester, Stopford Building, Oxford Road, Manchester, M13 9PT, UK. amin.rostami@manchester.ac.uk.|Simcyp Limited (a Certara Company), Blades Enterprise Centre, Sheffield, UK. amin.rostami@manchester.ac.uk.
authors: Amin
authors: http://orcid.org/0000-0003-3917-844X
authors: A
authors: Rostami-Hodjegan
mesh_terms: D000818:Animals; D003226:Congresses as Topic; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*
chemical_list: D004364:Pharmaceutical Preparations
keywords: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism