An innovative phase I study in healthy subjects to determine the mass balance, elimination, metabolism, and absolute bioavailability of mitapivat

• Published in: Clinical and translational science Vol. 16; no. 10; pp. 2021 - 2032
• Main Authors: Prakash, Chandra, Mangus, Heidi, Yan, Yan, Yang, Hua, Iyer, Varsha
• Format: Journal Article
• Language: English
• Published: Hoboken John Wiley & Sons, Inc 01.10.2023; John Wiley and Sons Inc; Wiley
• Subjects: Adenosine triphosphate; Adults; Allosteric properties; Anemia; Antibiotics; Bioavailability; Blood; Dealkylation; Drug dosages; Enzymes; Erythrocytes; FDA approval; Feces; Hemolytic anemia; Kinases; Metabolic pathways; Metabolism; Metabolites; Mutation; Permeability; Pharmacokinetics; Piperazine; Pyruvate kinase; Pyruvic acid; Radioactivity; Sulfonamides; Urine; United States > US
• ISSN: 1752-8054; 1752-8062; 1752-8062
• DOI: 10.1111/cts.13609

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 C 6 ]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 C 6 ]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 AUC 0–24 and AUC 0–72 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.