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The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Abrocitinib, a Selective Janus Kinase Inhibitor, in Humans

Jonathan N. Bauman, Angela C. Doran, Amanda King-Ahmad, Raman Sharma, Gregory S. Walker, Jian Lin, Tsung H Lin, Jean-Baptiste Telliez, Sakambari Tripathy, Theunis C. Goosen, Christopher Banfield, Bimal K Malhotra and Martin E Dowty
Drug Metabolism and Disposition June 14, 2022, DMD-AR-2022-000829; DOI: https://doi.org/10.1124/dmd.122.000829
Jonathan N. Bauman
1PDM, Pfizer Global R&D, United States
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Angela C. Doran
2Medicine Design - ADME Sciences, Pfizer, United States
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Amanda King-Ahmad
3Medicine Design, Pfizer Inc, United States
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Raman Sharma
4PDM Biotransformation, Pfizer, United States
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Gregory S. Walker
5PDM, Pfizer, United States
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Jian Lin
6PDM, Pfizer Inc, United States
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Tsung H Lin
7Inflammation and Immunology, Pfizer Inc, United States
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Jean-Baptiste Telliez
7Inflammation and Immunology, Pfizer Inc, United States
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Sakambari Tripathy
8Clinical Pharmacology, Pfizer Inc, United States
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Theunis C. Goosen
9Pharmacokinetics, Dynamics & Metabolism, Pfizer, Inc, United States
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Christopher Banfield
8Clinical Pharmacology, Pfizer Inc, United States
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Bimal K Malhotra
8Clinical Pharmacology, Pfizer Inc, United States
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Martin E Dowty
10Pfizer Inc, United States
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  • ORCID record for Martin E Dowty
  • For correspondence: martin.dowty@pfizer.com
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    • Supplemental Data -

      Supplemental Methods

      Supplemental Table S1. LC-MS/MS Conditions for Metabolite Profiling and 14C-Abrocitinib Quantitation.

      Supplemental Table S2. LC-MS/MS Conditions for Isolation of Metabolites M6 and M7 - Initial Assessment.

      Supplemental Table S3. LC-MS/MS Conditions for Isolation of Metabolites M6 and M7 - Initial Fractionation.

      Supplemental Table S4. LC-MS/MS Conditions for Isolation of Metabolites M6 and M7 - Analysis of Fractions.

      Supplemental Table S5. LC-MS/MS Conditions for Isolation of Metabolites M6 and M7 – Final Fractionation.

      Supplemental Table S6. LC-MS/MS Conditions for Abrocitinib in Plasma.

      Supplemental Table S7. LC-MS/MS Conditions for In Vitro Hepatocyte Fractional Metabolism

      Supplemental Table S8. LC-MS/MS conditions for in vitro CYP450 assignment (Enzyme kinetics and chemical inhibition)

      Supplemental Table S9. LC-MS/MS conditions for abrocitinib in plasma protein binding and blood-to-plasma ratio studies.

      Supplemental Table S10. LC-MS/MS conditions for M1 in plasma protein binding and blood-to-plasma ratio studies.

      Supplemental Table S11. LC-MS/MS conditions for M2 in plasma protein binding and blood-to-plasma ratio studies.

      Supplemental Table S12. Incidence of treatment-emergent mild adverse events.

      Supplemental Table S13. Diagnostic MS product ions used for abrocitinib and proposed metabolite structures.

      Supplemental Figure S1. 1H13C HMBC spectrum (left) and 1H1H COSY spectrum (right) of M6 (PF-07095462, 370, m/z 370) metabolite isolated from pooled human urine.

      Supplemental Figure S2. 1H13C HMBC spectrum (left) and 1H1H COSY spectrum (right) of M7 (PF-06737821, 354-1, m/z 354) metabolite isolated from pooled human urine.

      Supplemental Figure S3. Radiochromatogram following 30-minute incubation of 1 µM 14C-abroctinib (PF04965842) in human hepatocytes (0.75 million cells/mL)

      Supplemental Figure S4. Enzyme kinetic plots for primary metabolites M1 (A), M2/M3 (B), M4 (C), and 149 (D) and secondary metabolites M7 (E), 358-1 (F), and 372-1 (G) from abrocitinib metabolism.

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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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OtherArticle

Human ADME properties of abrocitinib

Jonathan N. Bauman, Angela C. Doran, Amanda King-Ahmad, Raman Sharma, Gregory S. Walker, Jian Lin, Tsung H Lin, Jean-Baptiste Telliez, Sakambari Tripathy, Theunis C. Goosen, Christopher Banfield, Bimal K Malhotra and Martin E Dowty
Drug Metabolism and Disposition June 14, 2022, DMD-AR-2022-000829; DOI: https://doi.org/10.1124/dmd.122.000829

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OtherArticle

Human ADME properties of abrocitinib

Jonathan N. Bauman, Angela C. Doran, Amanda King-Ahmad, Raman Sharma, Gregory S. Walker, Jian Lin, Tsung H Lin, Jean-Baptiste Telliez, Sakambari Tripathy, Theunis C. Goosen, Christopher Banfield, Bimal K Malhotra and Martin E Dowty
Drug Metabolism and Disposition June 14, 2022, DMD-AR-2022-000829; DOI: https://doi.org/10.1124/dmd.122.000829
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