Dataset Information

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

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 (F_reab) and renal excretion clearance (CL_R) 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 CL_R was collated for 157 drugs. A subset of 45 drugs was selected for model validation; for those, Caco-2 permeability (P_app) data were measured under pH6.5-7.4 gradient conditions and used to predict F_reab and subsequently CL_R. An empirical calibration approach was proposed to account for the effect of inter-assay/laboratory variation in P_app on the IVIVE of F_reab.

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 CL_R 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 CL_R (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 CL_R. Physiological basis of the model proposed allows its application in future mechanistic kidney models in preclinical species and human.

SUBMITTER: Scotcher D

PROVIDER: S-EPMC5074076 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Scotcher Daniel D Jones Christopher C Rostami-Hodjegan Amin A Galetin Aleksandra A

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 20160328

<h4>Purpose</h4>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 (F<sub>reab</sub>) and renal excretion clearance (CL<sub>R</sub>) from in vitro permeability data and tubular physiological parameters.<h4>Methods</h4>Model system parameters were informed by physiological data collated following extensive litera ...[more]

PMID: 27033147

Similar Datasets

Project description:Minimal physiologically-based pharmacokinetic (mPBPK) models provide a sensible modeling approach when fitting only plasma (or blood) data yielding physiologically-relevant PK parameters that may provide more practical value than parameters of mammillary models. We propose a second-generation mPBPK model specifically for monoclonal antibodies (mAb) by including (lumping) several essential components of mAb PK used in full PBPK models. These components include convection as the primary mechanism of antibody movement from plasma into tissues and return to plasma with interstitial fluid as the major extravascular distribution space. The model divides tissue spaces into two groups according to their vascular endothelial structure, leaky and tight, which consequently allows discernment of two types and general sites of distribution. This mPBPK model was applied to two mAbs in mice and ten mAbs with linear kinetics in humans. The model captured their plasma PK profiles well with predictions of concentrations in interstitial fluid for two types of tissues. Predictions of tissue concentrations for mAb 7E3 and 8C2 were consistent with actual measurements in mice, indicating the feasibility of this model in assessing extravascular distribution in the two categories of tissues. The vascular reflection coefficients (σ₁) of tight tissues (V(tight)) ranged 0.883-0.987 and coefficients (σ₂) for leaky tissues (V(leaky)) ranged 0.311 to 0.837. The plasma clearance (CL(p)) varied among the mAbs in humans from 0.0054 to 0.03 L/h. In addition, applying this model generates parameters for mAb transcapillary escape rates and assesses major sites of elimination. Four of ten mAbs exhibited better fitting statistics premised on elimination from interstitial fluid than from plasma. This approach allows comparisons of mAb PK when only plasma data are available, provides more realistic parameters and predictions than mammillary models, and may provide an intermediate step towards utilizing full PBPK models for mAbs.

Project description:Background and objectivesThe estimated glomerular filtration rate (eGFR) is a crucial parameter in heart failure. Much less is known about the importance of tubular function. We addressed the effect of tubular maximum phosphate reabsorption capacity (TmP/GFR), a parameter of proximal tubular function, in patients with heart failure.Design, setting, participants, & measurementsWe established TmP/GFR (Bijvoet formula) in 2085 patients with heart failure and studied its association with deterioration of kidney function (>25% eGFR decrease from baseline) and plasma neutrophil gelatinase-associated lipocalin (NGAL) doubling (baseline to 9 months) using logistic regression analysis and clinical outcomes using Cox proportional hazards regression. Additionally, we evaluated the effect of sodium-glucose transport protein 2 (SGLT2) inhibition by empagliflozin on tubular maximum phosphate reabsorption capacity in 78 patients with acute heart failure using analysis of covariance.ResultsLow TmP/GFR (<0.80 mmol/L) was observed in 1392 (67%) and 21 (27%) patients. Patients with lower TmP/GFR had more advanced heart failure, lower eGFR, and higher levels of tubular damage markers. The main determinant of lower TmP/GFR was higher fractional excretion of urea (P<0.001). Lower TmP/GFR was independently associated with higher risk of plasma NGAL doubling (odds ratio, 2.20; 95% confidence interval, 1.05 to 4.66; P=0.04) but not with deterioration of kidney function. Lower TmP/GFR was associated with higher risk of all-cause mortality (hazard ratio, 2.80; 95% confidence interval, 1.37 to 5.73; P=0.005), heart failure hospitalization (hazard ratio, 2.29; 95% confidence interval, 1.08 to 4.88; P=0.03), and their combination (hazard ratio, 1.89; 95% confidence interval, 1.07 to 3.36; P=0.03) after multivariable adjustment. Empagliflozin significantly increased TmP/GFR compared with placebo after 1 day (P=0.004) but not after adjustment for eGFR change.ConclusionsTmP/GFR, a measure of proximal tubular function, is frequently reduced in heart failure, especially in patients with more advanced heart failure. Lower TmP/GFR is furthermore associated with future risk of plasma NGAL doubling and worse clinical outcomes, independent of glomerular function.

Dataset Information

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

Purpose

Methods

Results

Conclusions

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets