An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat
Abstract 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 ad...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-10-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13609 |
| _version_ | 1797657467338883072 |
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| author | Chandra Prakash Heidi Mangus Yan Yan Hua Yang Varsha Iyer |
| author_facet | Chandra Prakash Heidi Mangus Yan Yan Hua Yang Varsha Iyer |
| author_sort | Chandra Prakash |
| collection | DOAJ |
| description | Abstract 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 [14C]mitapivat and a concomitant intravenous ~0.1 mg microdose of [13C6]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 [13C6]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). [14C]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 [14C]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. |
| first_indexed | 2024-03-11T17:46:03Z |
| format | Article |
| id | doaj.art-7bf42c7b47144d6abd8c8ab3c3facd67 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-11T17:46:03Z |
| publishDate | 2023-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-7bf42c7b47144d6abd8c8ab3c3facd672023-10-18T07:31:18ZengWileyClinical and Translational Science1752-80541752-80622023-10-0116102021203210.1111/cts.13609An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivatChandra Prakash0Heidi Mangus1Yan Yan2Hua Yang3Varsha Iyer4Agios Pharmaceuticals Cambridge Massachusetts USAAgios Pharmaceuticals Cambridge Massachusetts USAAgios Pharmaceuticals Cambridge Massachusetts USAAgios Pharmaceuticals Cambridge Massachusetts USAAgios Pharmaceuticals Cambridge Massachusetts USAAbstract 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 [14C]mitapivat and a concomitant intravenous ~0.1 mg microdose of [13C6]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 [13C6]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). [14C]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 [14C]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.https://doi.org/10.1111/cts.13609 |
| spellingShingle | Chandra Prakash Heidi Mangus Yan Yan Hua Yang Varsha Iyer An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat Clinical and Translational Science |
| title | An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat |
| title_full | An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat |
| title_fullStr | An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat |
| title_full_unstemmed | An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat |
| title_short | An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat |
| title_sort | innovative phase i study in healthy subjects to determine the mass balance elimination metabolism and absolute bioavailability of mitapivat |
| url | https://doi.org/10.1111/cts.13609 |
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