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Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2′-methylguanosine-5′-monophosphate, in the monkey and formulation optimization for human exposure

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Abstract

IDX184 is a phosphoramidate prodrug of 2′-methylguanosine-5′-monophosphate, developed to treat patients infected with hepatitis C virus. A mass balance study of radiolabeled IDX184 and pharmacokinetic studies of IDX184 in portal vein-cannulated monkeys revealed relatively low IDX184 absorption but higher exposure of IDX184 in the portal vein than in the systemic circulation, indicating >90 % of the absorbed dose was subject to hepatic extraction. Systemic exposures to the main metabolite, 2′-methylguanosine (2′-MeG), were used as a surrogate for liver levels of the pharmacologically active entity 2′-MeG triphosphate, and accordingly, systemic levels of 2′-MeG in the monkey were used to optimize formulations for further clinical development of IDX184. Capsule formulations of IDX184 delivered acceptable levels of 2′-MeG in humans; however, the encapsulation process introduced low levels of the genotoxic impurity ethylene sulfide (ES), which necessitated formulation optimization. Animal pharmacokinetic data guided the development of a tablet with trace levels of ES and pharmacokinetic performance equal to that of the clinical capsule in the monkey. Under fed conditions in humans, the new tablet formulation showed similar exposure to the capsule used in prior clinical trials.

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Abbreviations

AUC:

Area under the plasma concentration-time curve

BQL:

Below the limit of quantification

C max :

Maximum observed plasma concentration

CI:

Confidence interval

ES:

Ethylene sulfide

FaSSGF/FeSSGF:

Fasted or fed-state simulated gastric fluid

FaSSIF/FeSSIF:

Fasted or fed-state simulated intestinal fluid

HCV:

Hepatitis C virus

2′-MeG:

2′-Methylguanosine

MP:

Monophosphate

NI:

Nucleoside inhibitors

PEG:

Polyethylene glycol

ppm:

Parts per million

T 1/2 :

Apparent terminal half-life

TP:

Triphosphate

TTC:

Threshold of toxicological concern

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Acknowledgments

The authors would like to thank Emerson Resources for performing tablet development and GMP manufacturing, SNBL, Xenometrics and Covance for in-life phases of the in vivo studies, and PharmaNet USA for bioanalytical analyses. Also the authors would like to thank Dr. Xiao-Jian Zhou and other members of the Idenix clinical team for providing the clinical data as well as thank the healthy volunteers who participated in this study.

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Authors and Affiliations

  1. Idenix Pharmaceuticals, 320 Bent Street, 4th Floor, Cambridge, MA, 02141, USA

    Xin-Ru Pan-Zhou, Benjamin A. Mayes, Hassan Rashidzadeh, Rahela Gasparac, Steven Smith, Sanjeev Bhadresa, Kusum Gupta, Marita Larsson Cohen, Charlie Bu, Steven S. Good, Adel Moussa & Roger Rush

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  1. Xin-Ru Pan-Zhou
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  2. Benjamin A. Mayes
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Correspondence to Xin-Ru Pan-Zhou.

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Pan-Zhou, XR., Mayes, B.A., Rashidzadeh, H. et al. Pharmacokinetics of IDX184, a liver-targeted oral prodrug of 2′-methylguanosine-5′-monophosphate, in the monkey and formulation optimization for human exposure. Eur J Drug Metab Pharmacokinet 41, 567–574 (2016). https://doi.org/10.1007/s13318-015-0267-4

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  • DOI: https://doi.org/10.1007/s13318-015-0267-4

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