Phase I study of orally administered 14 Carbon-isotope labelled-vistusertib (AZD2014), a dual TORC1/2 kinase inhibitor, to assess the absorption, metabolism, excretion, and pharmacokinetics in patients with advanced solid malignancies

• Published in: Cancer chemotherapy and pharmacology Vol. 83; no. 4; p. 787
• Main Authors: MacDonald, Alexander, Scarfe, Graeme, Magirr, Dominic, Sarvotham, Tinnu, Charlton, Julie, Brugger, Wolfram, Dean, Emma
• Format: Journal Article
• Language: English
• Published: Germany 01.04.2019
• Subjects: Administration, Oral; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Area Under Curve; Benzamides - administration & dosage; Benzamides - pharmacokinetics; Carbon Radioisotopes; Female; Humans; Male; Mechanistic Target of Rapamycin Complex 1 - antagonists & inhibitors; Mechanistic Target of Rapamycin Complex 2 - antagonists & inhibitors; Middle Aged; Morpholines - administration & dosage; Morpholines - pharmacokinetics; Neoplasms - drug therapy; Neoplasms - pathology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; AZD2014; Phase I; ADME; Vistusertib; Metabolism; Solid malignancies
• ISSN: 1432-0843

Vistusertib is an orally bioavailable dual target of rapamycin complex (TORC) 1/2 kinase inhibitor currently under clinical investigation in various solid tumour and haematological malignancy settings. The pharmacokinetic, metabolic and excretion profiles of Carbon-isotope ( C)-labelled vistusertib were characterised in this open-label phase I patient study. Four patients with advanced solid malignancies received a single oral solution dose of C-labelled vistusertib. Blood, urine, faeces, and saliva samples were collected at various time points during the 8-day in-patient period of the study. Safety and preliminary efficacy were also assessed. C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (T ) < 1.2 h in all subjects). Overall, > 90% of radioactivity was recovered with the majority recovered as metabolites in faeces (on average 80% vs. 12% recovered in urine). The majority of circulating radioactivity (~ 78%) is unchanged vistusertib. Various morpholine-ring oxidation metabolites and an N-methylamide circulate at low concentrations [each < 10% area under the concentration-time curve from zero to infinity (AUC )]. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis. The pharmacokinetic (PK) profile of vistusertib is similar to previous studies using the same dosing regimen in solid malignancy patients. The majority of vistusertib elimination occurred via hepatic metabolic routes.