Pharmacokinetics, Mass Balance, Tissue Distribution, Metabolism, and Excretion of [¹⁴C]Aficamten Following Single Oral Dose Administration to Rats

ABSTRACT

1. The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [¹⁴C]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.

2. [¹⁴C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-hours (AUC_0-48). Plasma t_max was 4-hours and the t_1/2 of total plasma radioactivity was 5.8-hours.

3. Tissues showing highest C_max exposures were myocardium and semitendinosus muscle.

4. Most [¹⁴C]aficamten-derived radioactivity was excreted within 48-hours post-administration. Mean cumulative recovery in urine and feces over 168-hours was 8.3% and 90.7%, respectively.

5. In urine and bile, unchanged aficamten was detected at <0.1 and <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.

6. [¹⁴C]Aficamten was metabolized 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 feces 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 content solution.

Keywords:

• aficamten
• quantitative whole-body autoradiography
• metabolite identification
• pharmacokinetics
• excretion
• gut bacteria
• reduction
• 1,2,4-oxadiazole

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