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

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 drugdrug 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.KEY WORDS: active renal excretion; human kidney transporters; human renal drug clearance; kidney disease; non-hepatic drug metabolism.

Delineating the Role of Various Factors in Renal Disposition of Digoxin through Application of Physiologically Based Kidney Model to Renal Impairment Populations

“…Use of PBPK kidney models is challenged by a lack of physiological data to inform system parameters and scaling factors, the need for various in vitro data, and availability of suitable clinical data for the drug and population(s) of interest (Scotcher et al, 2016a,b). In an attempt to overcome such challenges in the current study, digoxin was selected as a model drug because of availability of in vitro data and ample clinical data (both plasma and urine) measured in healthy subjects and special populations (e.g., elderly and renal impairment).…”

Advances in predictive in vitro models of drug-induced nephrotoxicity

“…However, animal pharmacokinetic profiles often differ considerably from those of humans; hence, animal models are often poor predictors of adverse drug effects of drug disposition in humans 100,101 . This mismatch between animal and human outcomes is largely due to the many differences in drug transporter and metabolizing enzyme expression between species 102 .…”

“…As nephrotoxicity models become more physiologically relevant, their clinical predictive value will lie in screening not only for single drug effects but also for drug–drug interactions and the effects of individual variations such as the effects of underlying kidney disease or CYP enzyme polymorphisms on drug metabolism and toxicity 100,149,150 . Such analyses will require in vitro-to-in vivo extrapolations, involving mathematical models that can numerically simulate the behaviour of a drug in a complex system using results obtained experimentally in an in vitro system as the input parameter.…”

“…Such analyses will require in vitro-to-in vivo extrapolations, involving mathematical models that can numerically simulate the behaviour of a drug in a complex system using results obtained experimentally in an in vitro system as the input parameter. The success of these mechanistic models is highly dependent on in-depth quantitative knowledge of renal physiology, such as relevant flow rates, the total number of nephrons and cells in a kidney, and absolute protein expression levels of transporters and enzymes 100,151 . In physiologically based pharmacokinetic modelling, drug pharmacokinetics or toxicokinetics can be predicted in silico by incorporating relevant drug disposition data such as renal drug metabolism and renal accumulation during excretion 152 .…”

Systems Toxicology: Real World Applications and Opportunities

“…106 Also, the risk of human nephrotoxicity can be estimated from animal studies by modeling drug-specific transporters to derive local kidney concentrations. 107 …”