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<p>This study investigated the pharmacokinetics, mass balance, and metabolism of [<sup>14</sup>C]FCN-437c, a selective and potent CDK4/6 inhibitor, in humans. Six healthy male Chinese subjects were administered a single oral dose of 200 mg [<sup>14</sup>C]FCN-437c (120 µCi), and plasma, urine, and feces samples were collected up to 456&#xa0;h post-dose. The geometric mean <i>C</i><sub>max</sub> of radioactivity in plasma and blood were 706 and 557 ng eq./mL, respectively, with a median <i>T</i><sub>max</sub> of 5.0&#xa0;h and a geometric mean t<sub>1/2</sub> of 56.5&#xa0;h in plasma. The primary route of elimination was fecal excretion, accounting for a mean of 77.16% of the dose, whereas urinary excretion constituted a mean of 19.19% of the administered radioactivity. UHPLC-HRMS analysis identified 12 metabolites in human plasma, urine, and feces, with 8 of them being phase I metabolites, and the major metabolic pathways were mono-oxidation and <i>O</i>-dealkylation. Additionally, 4 phase II metabolites were identified, including two glucuronides, one glutathione conjugate, and one cysteine conjugate. The study provides insights into the metabolic stability and clearance mechanisms of FCN-437c in human, which are essential for its further clinical development and dosing regimens.</p>

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Pharmacokinetics, mass balance, and metabolism of [14C]FCN-437c, a selective and potent CDK4/6 inhibitor in humans

  • 期刊论文

  • 发表日期：

    2025年5月26日

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  • Lei Gao,
  • Sheng Ma,
  • Shu Yan,
  • Hua Zhang,
  • Ling Tian,
  • Lize Li,
  • Lei Diao,
  • Liyan Miao,
  • Xiaoran Yang,
  • Xingxing Diao

摘要

This study investigated the pharmacokinetics, mass balance, and metabolism of [14C]FCN-437c, a selective and potent CDK4/6 inhibitor, in humans. Six healthy male Chinese subjects were administered a single oral dose of 200 mg [14C]FCN-437c (120 µCi), and plasma, urine, and feces samples were collected up to 456 h post-dose. The geometric mean Cmax of radioactivity in plasma and blood were 706 and 557 ng eq./mL, respectively, with a median Tmax of 5.0 h and a geometric mean t1/2 of 56.5 h in plasma. The primary route of elimination was fecal excretion, accounting for a mean of 77.16% of the dose, whereas urinary excretion constituted a mean of 19.19% of the administered radioactivity. UHPLC-HRMS analysis identified 12 metabolites in human plasma, urine, and feces, with 8 of them being phase I metabolites, and the major metabolic pathways were mono-oxidation and O-dealkylation. Additionally, 4 phase II metabolites were identified, including two glucuronides, one glutathione conjugate, and one cysteine conjugate. The study provides insights into the metabolic stability and clearance mechanisms of FCN-437c in human, which are essential for its further clinical development and dosing regimens.