Pharmacokinetics, mass balance, tissue distribution, metabolism, and excretion of [<sup>14</sup>C]aficamten following single oral dose administration to rats
Creators: name: Grillo, Mark P.
name: Sukhun, Rajaa
name: Bashir, Mohammad
name: Ashcraft, Luke
name: Morgan, Bradley P.
Publisher: name: Taylor & Francis
Year: 2024
Subjects: subject: Biochemistry
subject: Physical Sciences not elsewhere classified
subject: Microbiology
subject: FOS: Biological sciences
subject: Cell Biology
subject: Physiology
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Ecology
subject: Marine Biology
subject: Cancer
subject: Inorganic Chemistry
subject: FOS: Chemical sciences
subject: Virology
subject: Computational Biology

description: The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [<sup>14</sup>C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats.[<sup>14</sup>C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC<sub>0–48</sub>). Plasma <i>t</i><sub>max</sub> was 4-h and the <i>t</i><sub>1/2</sub> of total plasma radioactivity was 5.8-h.Tissues showing highest C<sub>max</sub> exposures were myocardium and semitendinosus muscle.Most [<sup>14</sup>C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively.In urine and bile, unchanged aficamten was detected at &lt;0.1 and &lt;0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed.[<sup>14</sup>C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution. The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [<sup>14</sup>C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats. [<sup>14</sup>C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC<sub>0–48</sub>). Plasma <i>t</i><sub>max</sub> was 4-h and the <i>t</i><sub>1/2</sub> of total plasma radioactivity was 5.8-h. Tissues showing highest C<sub>max</sub> exposures were myocardium and semitendinosus muscle. Most [<sup>14</sup>C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively. In urine and bile, unchanged aficamten was detected at &lt;0.1 and &lt;0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed. [<sup>14</sup>C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution.