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13.02.2019 | Original Article | Ausgabe 4/2019

Cancer Chemotherapy and Pharmacology 4/2019

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

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 4/2019
Autoren:
Alexander MacDonald, Graeme Scarfe, Dominic Magirr, Tinnu Sarvotham, Julie Charlton, Wolfram Brugger, Emma Dean
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Abstract

Purpose

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 14Carbon-isotope (14C)-labelled vistusertib were characterised in this open-label phase I patient study.

Methods

Four patients with advanced solid malignancies received a single oral solution dose of 14C-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.

Results

14C-labelled vistusertib was rapidly absorbed following administration (time to maximum concentration (Tmax) < 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 (AUC0–∞)]. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.

Conclusions

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.

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