Development and validation of an LC-MS/MS assay for the quantification of Miransertib in human plasma and clinical...

Proteus syndrome is a rare genetic disorder characterized by progressive, abnormal overgrowth that can affect any organ or tissue in the body. This abnormality is caused by a mosaic activating variant in AKT1 that encodes a key serine/threonine kinase of the phosphoinositide-3-kinase (P13K)/AKT signaling pathway and is involved in cell growth, survival, and metabolism. Miransertib (MK-7075, formerly ARQ 092) is a novel, orally bioavailable allosteric pan-AKT inhibitor that selectively targets AKT1, AKT2, and AKT3, demonstrating potent suppression of AKT signaling and tumor growth in murine xenograft models with dysregulated signaling pathways. It has also been evaluated as a potential therapeutic option for individuals with Proteus syndrome, both in pre-clinical studies and in clinical trials. In this study, we have developed and validated a sensitive, robust, and specific LC-MS/MS method for quantifying miransertib in human plasma. The calibration curve ranged from 0.5 to 500 ng/mL in human plasma with a linearity of r² = 0.9945 ± 0.0019 across multiple days. Accuracy of assay ranged from -3.38 to 3.53% and precision was between 2.90 and 8.42%. Miransertib also showed excellent stability following multiple freeze-thaw cycles, during bench-top storage, and while on the autosampler overnight. This method enabled us to assess the pharmacokinetic parameters of participants enrolled in a phase II clinical trial (NCT04316546).