4.4 Article

Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [14C] SHC014748M in healthy Chinese subjects following oral administration

Journal

CANCER CHEMOTHERAPY AND PHARMACOLOGY
Volume 91, Issue 2, Pages 143-156

Publisher

SPRINGER
DOI: 10.1007/s00280-022-04493-5

Keywords

SHC014748M; C-14; Metabolism; Pharmacokinetics; Excretion

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In this study, the pharmacokinetics, mass balance, metabolism and excretion of SHC014748M in Chinese male subjects were investigated. The results showed that SHC014748M was absorbed, metabolized and excreted, with fecal excretion being the main elimination route.
Purpose SHC014748M is a potent, novel selective PI3K delta isoform inhibitor and is proposed for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. This study investigated the pharmacokinetics, mass balance, metabolism and excretion of SHC014748M in Chinese male subjects following a single oral dose of 150 mg (100 mu Ci) [C-14] SHC014748M. Methods Six healthy Chinese male subjects administrated an oral suspension of 150 mg (100 mu Ci) [C-14] SHC014748M and the samples of blood, urine and feces were collected for measuring. Liquid chromatography-tandem mass spectrometry and liquid scintillation counter were utilized to obtain mass balance and the pharmacokinetic data. Results The median T-max for [C-14]-radioactivity was 1.6 +/- 0.5 h after the oral administration of [C-14] SHC014748M and the mean C-max was 3863 +/- 354 ng Eq./mL in plasma, while the mean C-max, t(1/2) values and AUC(0-infinity) values for total radioactivity in whole blood were 2466 +/- 518 ng Eq./mL, 32.2 +/- 30.5 h and 66,236 +/- 44,232 h * ng Eq./mL, respectively. Fecal excretion was proposed as the predominant elimination route, accounting for a mean of 90.68 +/- 11.38% of the administered dose, whereas the mean urine excretion was 6.00 +/- 1.48% within 336 h post-dose. The proposed major metabolic pathway of [C-14] SHC014748M in the human body were as follows: (I) monooxidation, (II) glucuronide acid conjugation, and (III) monoxide-hydrogenation. Conclusions SHC014748M was absorbed, metabolized and excreted with unchanged SHC014748M as its main circulating component in plasma following oral administration. In addition, it was speculated that fecal excretion was the principal excretion pathway; meanwhile, monohydroxy, glucuronide conjugation, oxygen, and hydrogenation were the major clearance pathways of SHC014748M through urine and/or feces.

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