Novel minimal physiologically-based model for the prediction of passive tubular reabsorption and renal excretion clearance

https://doi.org/10.1016/j.ejps.2016.03.018Get rights and content
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Abstract

Purpose

Develop a minimal mechanistic model based on in vitro–in vivo extrapolation (IVIVE) principles to predict extent of passive tubular reabsorption. Assess the ability of the model developed to predict extent of passive tubular reabsorption (Freab) and renal excretion clearance (CLR) from in vitro permeability data and tubular physiological parameters.

Methods

Model system parameters were informed by physiological data collated following extensive literature analysis. A database of clinical CLR was collated for 157 drugs. A subset of 45 drugs was selected for model validation; for those, Caco-2 permeability (Papp) data were measured under pH 6.5–7.4 gradient conditions and used to predict Freab and subsequently CLR. An empirical calibration approach was proposed to account for the effect of inter-assay/laboratory variation in Papp on the IVIVE of Freab.

Results

The 5-compartmental model accounted for regional differences in tubular surface area and flow rates and successfully predicted the extent of tubular reabsorption of 45 drugs for which filtration and reabsorption were contributing to renal excretion. Subsequently, predicted CLR was within 3-fold of the observed values for 87% of drugs in this dataset, with an overall gmfe of 1.96. Consideration of the empirical calibration method improved overall prediction of CLR (gmfe = 1.73 for 34 drugs in the internal validation dataset), in particular for basic drugs and drugs with low extent of tubular reabsorption.

Conclusions

The novel 5-compartment model represents an important addition to the IVIVE toolbox for physiologically-based prediction of renal tubular reabsorption and CLR. Physiological basis of the model proposed allows its application in future mechanistic kidney models in preclinical species and human.

Abbreviations

AUC
area under the plasma concentration-time profile
BCRP
breast cancer resistance protein
CD
collecting duct
Cp
plasma concentration
CLR
renal excretion clearance
CLR, filt
renal filtration clearance
CLR, int,reab
intrinsic permeability clearance in renal tubule
CLR,sec
renal secretion clearance
DT
distal tubule
fu,p
fraction of drug unbound in plasma
Freab
fraction of the drug reabsorbed in the renal tubule
Freab
intermediate model parameter, representing the fraction of the equilibrium reached between unbound drug concentration in the plasma and urine
GFR
glomerular filtration rate
gmfe
geometric mean fold error
IVIVE
in vitro–in vivo extrapolation
LogD
octanol-buffer distribution coefficient
LoH
loop of Henle
MATE
multidrug and toxin extrusion protein
MRP
multidrug resistance protein
OAT
organic anion transporter
OCT
organic cation transporter
OATP
organic anion-transporting peptides
OCTN
organic cation/l-carnitine transporter
Papp
apparent permeability
PBPK
physiologically-based pharmacokinetic
P-gp
P-glycoprotein
PT
proximal tubule
RMSE
root mean squared error
TFR
tubular flow rate
TSA
tubular surface area

Keywords

In vitroin vivo extrapolation
Tubular reabsorption
Renal excretion clearance

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