Towards Further Verification of Physiologically-Based Kidney Models: Predictability of the Effects of Urine-Flow and Urine-pH on Renal Clearance.

Takanobu Matsuzaki,Adam S Darwich,Aleksandra Galetin,Amin Rostami-Hodjegan,Daniel Scotcher

doi:10.1124/jpet.118.251413

Abstract

In vitro-in vivo extrapolation (IVIVE) of renal excretory clearance (CLR) using the physiologically based kidney models can provide mechanistic insight into the interplay of multiple processes occurring in the renal tubule; however, the ability of these models to capture quantitatively the impact of perturbed conditions (e.g., urine flow, urine pH changes) on CLR has not been fully evaluated. In this work, we aimed to assess the predictability of the effect of urine flow and urine pH on CLR and tubular drug concentrations (selected examples). Passive diffusion clearance across the nephron tubule membrane was scaled from in vitro human epithelial cell line Caco-2 permeability data by nephron tubular surface area to predict the fraction reabsorbed and the CLR of caffeine, chloramphenicol, creatinine, dextroamphetamine, nicotine, sulfamethoxazole, and theophylline. CLR values predicted using mechanistic kidney model at a urinary pH of 6.2 and 7.4 resulted in prediction bias of 2.87- and 3.62-fold, respectively. Model simulations captured urine flow-dependent CLR, albeit with minor underprediction of the observed magnitude of change. The relationship between drug solubility, urine flow, and urine pH, illustrated in simulated intratubular concentrations of acyclovir and sulfamethoxazole, agreed with clinical data on tubular precipitation and crystal-induced acute kidney injury. This study represents the first systematic evaluation of the ability of the mechanistic kidney model to capture the impact of urine flow and urine pH on CLR and drug tubular concentrations with the aim of facilitating refinement of IVIVE-based mechanistic prediction of renal excretion.

Highlights

Together with the liver, the kidneys play a principal role in the excretion of a wide variety of xenobiotics, including drugs, metabolites, and toxins, as well as endogenous compounds
Some misspecification of the absorption phase may be apparent for some drugs, accurate description of oral absorption was not considered an essential feature of the model for the purpose of the current study, and further refinement of oral absorption was not performed
Models developed for the purpose of describing passive tubular reabsorption have allowed simulation of urine flow–dependent CLR of drugs with different permeability properties (Tang-Liu et al, 1983; Komiya, 1986; Mayer et al, 1988); these models did not account for the varying physiology of the renal tubule in a mechanistic and quantitative manner and lack the ability to simulate intra-tubular drug concentrations

Summary

Introduction

The kidneys play a principal role in the excretion of a wide variety of xenobiotics, including drugs, metabolites, and toxins, as well as endogenous compounds. Renal excretion can be defined as the elimination of unchanged solutes from the blood into the urine as a net result of the processes of glomerular filtration, tubular secretion, and tubular reabsorption (Tucker, 1981). Passive tubular reabsorption is a major process that controls the extent of renal excretion of many substances (Varma et al, 2009; Scotcher et al, 2016b). The magnitude of passive reabsorption depends on the lipophilicity and extent of ionization of a drug and physiologic properties, such as urine flow rate and the. A.R.-H. is an employee of Simcyp Limited (A Certara Company).

Objectives

Methods

Results

Conclusion