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Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD)

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Abstract

Purpose

This study was designed to verify a virtual population representing patients with nonalcoholic fatty liver disease (NAFLD) to support the implementation of a physiologically based pharmacokinetic (PBPK) modeling approach for prediction of disease-related changes in drug pharmacokinetics.

Methods

A virtual NAFLD patient population was developed in GastroPlus (v.9.8.2) by accounting for pathophysiological changes associated with the disease and proteomics-informed alterations in the abundance of metabolizing enzymes and transporters pertinent to drug disposition. The NAFLD population model was verified using exemplar drugs where elimination is influenced predominantly by cytochrome P450 (CYP) enzymes (chlorzoxazone, caffeine, midazolam, pioglitazone) or by transporters (rosuvastatin, 11C-metformin, morphine and the glucuronide metabolite of morphine).

Results

PBPK model predictions of plasma concentrations of all the selected drugs and hepatic radioactivity levels of 11C-metformin were consistent with the clinically-observed data. Importantly, the PBPK simulations using the virtual NAFLD population model provided reliable estimates of the extent of changes in key pharmacokinetic parameters for the exemplar drugs, with mean predicted ratios (NAFLD patients divided by healthy individuals) within 0.80- to 1.25-fold of the clinically-reported values, except for midazolam (prediction-fold difference of 0.72).

Conclusion

A virtual NAFLD population model within the PBPK framework was successfully developed with good predictive capability of estimating disease-related changes in drug pharmacokinetics. This supports the use of a PBPK modeling approach for prediction of the pharmacokinetics of new investigational or repurposed drugs in patients with NAFLD and may help inform dose adjustments for drugs commonly used to treat comorbidities in this patient population.

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Data availability

No new experimental data were generated in this simulation study. The PBPK models used to verify the virtual NAFLD patient population are available from the corresponding authors upon reasonable request.

Abbreviations

AUC:

Area under the plasma concentration–time curve

BCRP:

Breast cancer resistance protein

BMI:

Body mass index

CBT:

13C-caffeine breath test

CL/F:

Oral clearance

Cmax :

Peak plasma concentrations

Css,min :

Trough concentrations

CYP:

Cytochrome P450

M3G:

Morphine-3-glucuronide

MATE:

Multidrug and toxin extrusion

MRP:

Multidrug resistance-associated protein

NAFL:

Nonalcoholic fatty liver or simple steatosis

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

OATP:

Organic anion transporting polypeptides

OCT1:

Organic cation transporter 1

PBPK:

Physiologically based pharmacokinetic

PO:

Per os (Oral administration)

QSP:

Quantitative systems pharmacology

SUV:

Standardized uptake values

UGT:

Uridine 5’-diphospho-glucuronosyltransferase

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Acknowledgements

The authors are grateful to Drs. Viera Lukacova (PBPK Solutions, Simulations Plus, Inc.), and also Kyunghee Yang and James Beaudoin (Quantitative Systems Pharmacology Solutions, Simulations Plus, Inc.) for helpful suggestions and for providing feedback on the manuscript. We would like to thank Dr. Scott Siler (Quantitative Systems Pharmacology Solutions, Simulations Plus, Inc.) for scientific discussions on the NAFLD patient population. Dr. Ke Szeto (formerly at Simulations Plus, Inc.; current affiliation: Incyte Corporation) provided guidance and technical assistance during the initial stages of the project. Components of this work have been presented at the International Society for the Study of Xenobiotics (ISSX) and the Microsomes and Drug Oxidations (MDO) Joint Meeting in September 2022.

Funding

During this study, JA received financial support from Simulations Plus, Inc. for his postdoctoral training.

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  1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jeffry Adiwidjaja & Kim L. R. Brouwer

  2. Simulations Plus, Inc, Lancaster, CA, USA

    Jeffry Adiwidjaja & Jessica Spires

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  1. Jeffry Adiwidjaja
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  2. Jessica Spires
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Correspondence to Jessica Spires or Kim L. R. Brouwer.

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JS is an employee and shareholder of Simulations Plus, Inc. Following the completion of this study, JA joined Simulations Plus, Inc. as an employee. KLRB has received financial support for a PhD Studentship awarded to Dr. William Murphy from a Certara Simcyp 2020/2021 Grant and Partnership Scheme (GPS).

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Adiwidjaja, J., Spires, J. & Brouwer, K.L.R. Physiologically Based Pharmacokinetic (PBPK) Model Predictions of Disease Mediated Changes in Drug Disposition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD). Pharm Res 41, 441–462 (2024). https://doi.org/10.1007/s11095-024-03664-8

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