In Vitro–In Vivo Extrapolation Method to Predict Human Renal Clearance of Drugs

Kunze, Annett; Huwyler, Jörg; Poller, Birk; Gutmann, Heike; Camenisch, Gian

doi:10.1002/jps.23851

Cited by 38 publications

(55 citation statements)

References 24 publications

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“…Some studies have proposed the use of permeability data following apical-basolateral transport across Lewis lung carcinoma pig kidney (LLC-PK1) cells for the assessment of tubular reabsorption in the human proximal tubule (26). Methods for culturing primary renal tubule cells have been published for the remaining sections of the nephron tubule (loop of Henle through collecting duct), but these are not routinely used for permeability and drug transport studies, e.g.…”

Section: Measurement Of Renal Passive Tubular Permeability In Vitromentioning

confidence: 99%

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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ABSTRACT.The programme for the 2015 AAPS Annual Meeting and Exhibition (Orlando, FL; 25-29 October 2015) included a sunrise session presenting an overview of the state-of-the-art tools for in vitro-in vivo extrapolation (IVIVE) and mechanistic prediction of renal drug disposition. These concepts are based on approaches developed for prediction of hepatic clearance, with consideration of scaling factors physiologically relevant to kidney and the unique and complex structural organisation of this organ. Physiologically relevant kidney models require a number of parameters for mechanistic description of processes, supported by quantitative information on renal physiology (system parameters) and in vitro/in silico drug-related data. This review expands upon the themes raised during the session and highlights the importance of high quality in vitro drug data generated in appropriate experimental setup and robust system-related information for successful IVIVE of renal drug disposition. The different in vitro systems available for studying renal drug metabolism and transport are summarised and recent developments involving state-of-the-art technologies highlighted. Current gaps and uncertainties associated with system parameters related to human kidney for the development of physiologically based pharmacokinetic (PBPK) model and quantitative prediction of renal drug disposition, excretion, and/or metabolism are identified.

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Section: Measurement Of Renal Passive Tubular Permeability In Vitromentioning

confidence: 99%

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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“…In contrast, sufficient physiological data are available for scaling in vitro data using surface area to predict CL R,sec (22). The success of this approach may be hindered by any potential differences in the characteristics (e.g.…”

Section: Prediction Of Renal Excretion Of Drugs Within Pbpk Paradigmmentioning

confidence: 99%

“…protein expression, cell morphology) of the in vitro system and the kidney in vivo, if these are not accounted for. However, scaling of P app data from the Lewis lung carcinoma pig kidney (LLC-PK1) cell line by surface area was used to predict CL R of net secreted drugs with reasonable success using the wellstirred model (22). CL int , V max (when expressed per cm 2 ) and membrane permeability (expressed cm/s) data obtained using proximal tubule cell monolayers (e.g.…”

Section: Prediction Of Renal Excretion Of Drugs Within Pbpk Paradigmmentioning

confidence: 99%

“…Both active secretion and reabsorption can be described using well-stirred or parallel tube models, relating the intrinsic secretion clearance to the renal blood flow (secretion), or the tubular filtrate flow (reabsorption) (11,22). Few studies have compared different structures or refined versions of mechanistic kidney models in specific scenarios (19,37), and further studies of this nature are recommended.…”

Section: Prediction Of Renal Excretion Of Drugs Within Pbpk Paradigmmentioning

confidence: 99%

“…Mechanistic models have recently been developed that incorporate IVIVE of passive tubular reabsorption from in vitro P app data (22,23). In these models, tubular surface areas are used as IVIVE scaling factors to convert P app data to CL int (Table I).…”

Section: Prediction Of Renal Excretion Of Drugs Within Pbpk Paradigmmentioning

confidence: 99%

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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

Scotcher

Jones²,

Posada

et al. 2016

AAPS J

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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.

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Predictive Method Development: Challenges for Cosmetics and Genotoxicity as a Case Study

Ouédraogo

Nesslany

Simar

et al. 2014

Methods and Principles in Medicinal Chemistry

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In Vitro–In Vivo Extrapolation Method to Predict Human Renal Clearance of Drugs

Cited by 38 publications

References 24 publications

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

Key to Opening Kidney for In Vitro–In Vivo Extrapolation Entrance in Health and Disease: Part I: In Vitro Systems and Physiological Data

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

Predictive Method Development: Challenges for Cosmetics and Genotoxicity as a Case Study

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