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In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models

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ABSTRACT

Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters. In vitro inhibition studies were conducted using transporter transfected cells and membrane vesicles. The risk of clinical drug-drug interactions (DDIs) was assessed using simplified static models recommended by regulatory agencies. Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins. These models successfully predicted a total of 46 statin DDIs, including above DAA drugs and their fix-dose combination regimens. Predicted plasma area under curve ratio (AUCR) with and without perpetrator drugs was within ~ 2-fold of observed values. In contrast, simplified static R-value model resulted in increased false negative and false positive predictions when different prediction cut-off values were applied. Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate prediction of the risk and magnitude of DDIs with statins in early drug development and may help to improve the management of clinical DDIs for HCV drugs to ensure effective and safe HCV therapy.

GRAPHICAL ABSTRACT

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Abbreviations

ADME:

Absorption, distribution, metabolism, and excretion

AUCR:

Area under the curve ratio

AAFE:

Absolute average fold error

BCRP:

Breast cancer resistance protein

BSP:

Bromosulfophthalein

CYP:

Cytochrome P450

Cmax :

Maximum plasma concentration

DAA:

Direct-acting antiviral

DDI:

Drug-drug interaction

DME:

Drug metabolizing enzymes

ES:

Estrone sulfate

EMA:

European Medical Agency

FDA:

U.S. Food and Drug Administration

ft :

Fraction transported

Fa :

Fraction absorbed

Fg :

The fraction escaping intestinal metabolism

HCV:

Hepatitis C virus

Iin,max :

Maximal inhibition concentration at the liver inlet

I1u :

Mean steady state unbound Cmax

I2 :

Dose of the inhibitor (in mol)/250 mL

MDR:

Multidrug resistance

MTX:

Methotrexate

OATP:

Organic anion transporting polypeptide

OAT:

Organic anion transporter

OCT:

Organic cation transporter

P-gp:

P-glycoprotein

PK:

Pharmacokinetics

RMSE:

Root mean squared error

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Acknowledgements

We acknowledge Dr. Thomayant Prueksaritanont for valuable suggestions on study design. We also acknowledge Ms. Xiaoxin Cai and Dr. Jingjing Guo for technical assistance, and Drs. Lucinda Hittle and Alema Galijatovic-Idrizbegovic for critical review of the manuscript.

Funding

All studies conducted in this manuscript were sponsored by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

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  1. Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., RY800-D211, 126 East Lincoln Avenue, Rahway, New Jersey, 07065, USA

    Xiaoyan Chu, Grace Hoyee Chan, Robert Houle, Meihong Lin, Jocelyn Yabut & Christine Fandozzi

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  1. Xiaoyan Chu
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  2. Grace Hoyee Chan
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  3. Robert Houle
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  4. Meihong Lin
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Contributions

Participated in research design: Chu, Chan, Houle, Fandozzi

Conducted experiments: Chan, Houle, Lin

Contributed new reagents or analytic tools: NA

Performed data analysis: Chu, Chan, Houle, Lin, Yabut

Wrote or contributed to the writing of the manuscript: Chu, Chan, Houle, Yabut, Fandozzi

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Correspondence to Xiaoyan Chu.

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Chu, X., Chan, G.H., Houle, R. et al. In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models. AAPS J 24, 45 (2022). https://doi.org/10.1208/s12248-021-00677-8

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