An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat
© 2023 Agios, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics..
Mitapivat, a first-in-class, oral, small-molecule, allosteric activator of the red blood cell-specific form of pyruvate kinase (PKR), was approved for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. In this phase I mass balance study in healthy males, we administered a single ~120 mg oral dose of [14 C]mitapivat and a concomitant intravenous ~0.1 mg microdose of [13 C6 ]mitapivat. We determined (1) the routes of total radioactivity excretion, including the mass balance of total radioactivity in urine and feces; (2) the pharmacokinetics of mitapivat and [13 C6 ]mitapivat in plasma and total radioactivity in whole blood and plasma; (3) the absolute oral bioavailability of mitapivat; and (4) the metabolite profiles in plasma and excreta. Mean recovery of the radioactive dose was 89.1% (49.6% in urine and 39.6% in feces). [14 C]Mitapivat was rapidly absorbed and extensively metabolized as <4% of the total radioactive dose was excreted unaltered in urine and feces. Mean absolute oral bioavailability was 72.7%. A total of 17 metabolites were identified. Mitapivat accounted for 57% and 34% of plasma radioactivity in AUC0-24 and AUC0-72 pooled samples, respectively. The remaining radioactivity was attributable to several metabolites, each representing <10% of the total radioactivity in pooled samples; none were disproportionate metabolites as defined by the US Food and Drug Administration and International Conference on Harmonisation M3 guidelines. Metabolite structures suggest that the primary metabolic pathways for [14 C]mitapivat in humans include N-dealkylation of the cyclopropylmethyl moiety, oxygenation of the quinoline-8-sulfonamide, oxidation/unsaturation, scission of the piperazine moiety, and amide hydrolysis.
Medienart: |
E-Artikel |
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Erscheinungsjahr: |
2023 |
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Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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Enthalten in: |
Clinical and translational science - 16(2023), 10 vom: 30. Okt., Seite 2021-2032 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Prakash, Chandra [VerfasserIn] |
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Links: |
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Themen: |
2WTV10SIKH |
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Anmerkungen: |
Date Completed 23.10.2023 Date Revised 23.10.2023 published: Print-Electronic Citation Status MEDLINE |
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doi: |
10.1111/cts.13609 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM36095488X |
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520 | |a Mitapivat, a first-in-class, oral, small-molecule, allosteric activator of the red blood cell-specific form of pyruvate kinase (PKR), was approved for the treatment of hemolytic anemia in adults with pyruvate kinase (PK) deficiency. In this phase I mass balance study in healthy males, we administered a single ~120 mg oral dose of [14 C]mitapivat and a concomitant intravenous ~0.1 mg microdose of [13 C6 ]mitapivat. We determined (1) the routes of total radioactivity excretion, including the mass balance of total radioactivity in urine and feces; (2) the pharmacokinetics of mitapivat and [13 C6 ]mitapivat in plasma and total radioactivity in whole blood and plasma; (3) the absolute oral bioavailability of mitapivat; and (4) the metabolite profiles in plasma and excreta. Mean recovery of the radioactive dose was 89.1% (49.6% in urine and 39.6% in feces). [14 C]Mitapivat was rapidly absorbed and extensively metabolized as <4% of the total radioactive dose was excreted unaltered in urine and feces. Mean absolute oral bioavailability was 72.7%. A total of 17 metabolites were identified. Mitapivat accounted for 57% and 34% of plasma radioactivity in AUC0-24 and AUC0-72 pooled samples, respectively. The remaining radioactivity was attributable to several metabolites, each representing <10% of the total radioactivity in pooled samples; none were disproportionate metabolites as defined by the US Food and Drug Administration and International Conference on Harmonisation M3 guidelines. Metabolite structures suggest that the primary metabolic pathways for [14 C]mitapivat in humans include N-dealkylation of the cyclopropylmethyl moiety, oxygenation of the quinoline-8-sulfonamide, oxidation/unsaturation, scission of the piperazine moiety, and amide hydrolysis | ||
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700 | 1 | |a Iyer, Varsha |e verfasserin |4 aut | |
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