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Metabolism and pharmacokinetics characterization of metarrestin in multiple species

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Abstract

Purpose

Metarrestin is a first-in-class pyrrolo-pyrimidine-derived small molecule targeting a marker of genome organization associated with metastasis and is currently in preclinical development as an anti-cancer agent. Here, we report the in vitro ADME characteristics and in vivo pharmacokinetic behavior of metarrestin.

Methods

Solubility, permeability, and efflux ratio as well as in vitro metabolism of metarrestin in hepatocytes, liver microsomes and S9 fractions, recombinant cytochrome P450 (CYP) enzymes, and potential for CYP inhibition were evaluated. Single dose pharmacokinetic profiles after intravenous and oral administration in mice, rat, dog, monkey, and mini-pig were obtained. Simple allometric scaling was applied to predict human pharmacokinetics.

Results

Metarrestin had an aqueous solubility of 150 µM at pH 7.4, high permeability in PAMPA and moderate efflux ratio in Caco-2 assays. The compound was metabolically stable in liver microsomes, S9 fractions, and hepatocytes from six species, including human. Metarrestin is a CYP3A4 substrate and, in mini-pigs, is also directly glucuronidated. Metarrestin did not show cytochrome P450 inhibitory activity. Plasma concentration–time profiles showed low to moderate clearance, ranging from 0.6 mL/min/kg in monkeys to 48 mL/min/kg in mice and moderate to high volume of distribution, ranging from 1.5 L/kg in monkeys to 17 L/kg in mice. Metarrestin has greater than 80% oral bioavailability in all species tested. The excretion of unchanged parent drug in urine was < 5% in dogs and < 1% in monkeys over collection periods of ≥ 144 h; in bile-duct cannulated rats, the excretion of unchanged drug was < 1% in urine and < 2% in bile over a collection period of 48 h.

Conclusions

Metarrestin is a low clearance compound which has good bioavailability and large biodistribution after oral administration. Biotransformation appears to be the major elimination process for the parent drug. In vitro data suggest a low drug–drug interaction potential on CYP-mediated metabolism. Overall favorable ADME and PK properties support metarrestin’s progression to clinical investigation.

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Materials availability

Metarrestin is available from AOBIOUS, Glixx Laboratories Inc, US Biological Life Sciences under the name ML-246.

Abbreviations

ADME:

Absorption, distribution, metabolism and excretion

CLint :

Intrinsic clearance

CLp :

Plasma clearance

CLND:

Chemiluminescent nitrogen detection

CYP:

Cytochrome P450

F :

Bioavailability

HP-β-CD:

2-Hydroxypropyl-β-cyclodextrin

IV:

Intravenous

P app :

Apparent permeability

PK:

Pharmacokinetics

PNC:

Peri-nucleolar compartment

ROE:

Rule of exponents

SA:

Simple allometry

t 1/2 :

Elimination half-life

Vdss :

Volume of distribution at steady-state

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Funding

This research was supported in part by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health. This Research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (ZIA BC 011267), donations from ‘Running for Rachel’ and the Pomerenk family via the Rachel Guss and Bob Pomerenk Pancreas Cancer Research Fellowship. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

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Authors and Affiliations

  1. Division of Preclinical Innovation (DPI), National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20850, USA

    Elias C. Padilha, Pranav Shah, Amy Q. Wang, Marc D. Singleton, Emma A. Hughes, Kylie M. Konrath, Samarjit Patnaik, Juan Marugan & Xin Xu

  2. Rare Tumor Initiative (RTI), Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10-CCR, Room 2B-34D, Bethesda, MD, 20892, USA

    Dandan Li & Udo Rudloff

  3. Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD, USA

    Kelly A. Rice

Authors
  1. Elias C. Padilha
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  2. Pranav Shah
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  3. Amy Q. Wang
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  4. Marc D. Singleton
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  7. Kelly A. Rice
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  8. Kylie M. Konrath
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  9. Samarjit Patnaik
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  10. Juan Marugan
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  11. Udo Rudloff
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  12. Xin Xu
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Corresponding authors

Correspondence to Udo Rudloff or Xin Xu.

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Conflict of interest

SP and JM are Inventors on Patent entitled “Compounds and methods for the prevention and treatment of tumor metastasis and tumorigenesis” (US9663521B2). A provisional patent application entitled “Formulations and methods for the prevention and treatment of tumor metastasis and tumorigenesis” has been filed (WO2019222380A1). Inventors include UR, JM, and SP. All the other authors declare that they have no competing interest.

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280_2020_4042_MOESM1_ESM.pptx

Supplementary file1 Impact of metarrestin on CYP2 and CYP3 metabolism. Examined CYP isoform shown on top, known substrate and metabolite depicted on bottom. Impact by known inhibitor on CYP function (used as positive control) shown in blue curves, impact on CYP metabolism by metarrestin indicated by orange and red dose response curves (in triplicates).

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Padilha, E.C., Shah, P., Wang, A.Q. et al. Metabolism and pharmacokinetics characterization of metarrestin in multiple species. Cancer Chemother Pharmacol 85, 805–816 (2020). https://doi.org/10.1007/s00280-020-04042-y

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  • DOI: https://doi.org/10.1007/s00280-020-04042-y

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