A high-throughput LC-MS/MS method for simultaneous determination of lumateperone and its four metabolites in human
Hongjie Ding1,2, Bingda Wu3, Rui Wang4
1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China.
Abstract:
Lumateperone is an antipsychotic metabolised to four active metabolites IC200131, IC200161, IC200565 and IC201308, which are closely related to its clinical efficacy and safety.For evaluating the clinical pharmacokinetics of lumateperone and its active metabolites in Chinese subjects, a high-throughput LC-MS/MS method was developed and validated for the simultaneous quantification of lumateperone and its four metabolites in human plasma. Chromatographic separation was achieved using an alkaline mobile phase and a bidentate silane column (Zorbax Extend-C18) with two-step gradient elution, which overcame peak tailing and carryover while enabling rapid analysis. The calibration ranges were 0.100-80.0 ng/mL for lumateperone and IC200131, 0.0400-32.0 ng/mL for IC200161 and IC201308, and 0.150-30.0 ng/mL for IC200565.The validated method was successfully applied to a pharmacokinetic study of lumateperone tosylate capsules. The clinical trial was registered at the Chinese Clinical Trial Registry (identifier: CTR20242699). Under fasting conditions, the mean Cmax values were 30.6 ng/mL for lumateperone, with corresponding AUC0-t values of 72.8 h·ng/mL. Under fed conditions, food delayed absorption and decreased Cmax for all analytes.This study reports the first comprehensive pharmacokinetic profiles of lumateperone and its four active metabolites in Chinese subjects. The validated method provides a robust foundation for pharmacokinetic research of lumateperone in humans.
