PurposeBarasertib (AZD1152) is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA, a selective Aurora B kinase inhibitor that has shown preliminary activity in clinical studies of patients with acute myeloid leukemia (AML). The pharmacokinetic (PK), metabolic and excretion profiles of barasertib and barasertib-hQPA were characterized in this open-label Phase I study.MethodsFive patients with poor prognosis AML (newly diagnosed, relapsed or refractory) received barasertib 1,200 mg as a 7-day continuous infusion every 28 days. On Day 2 of Cycle 1 only, patients also received a 2-hour infusion of [14C]-barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed.ResultsBarasertib-hQPA was extensively distributed to tissues, with a slow rate of total clearance (CL = 31.4 L/h). Overall, 72–82 % of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51 %) compared with urine (mean = 27 %). The main metabolism pathways for barasertib were (1) cleavage of the phosphate group to form barasertib-hQPA, followed by oxidation and (2) loss of the fluoroaniline moiety to form barasertib-hQPA desfluoroaniline, followed by oxidation. One of the four patients evaluable for response entered complete remission. No new or unexpected safety findings were observed; the most common adverse events were nausea and stomatitis.ConclusionsThe PK profile of barasertib is similar to previous studies using the same dosing regimen in patients with AML. The majority of barasertib-hQPA clearance occurred via hepatic metabolic routes.

The main aim of the study was to investigate the distribution of radioactivity in the tissues and tumours using quantitative whole-body autoradiography (QWBA), together with a more detailed investigation of plasma and tumour samples, following administration of a single intravenous dose at 200 mg kg(-1) of 14C-ZD6126 to mice bearing subcutaneous Hras5 tumour xenografts. The study also included an assessment of tumour necrosis following administration of a single intravenous dose of non-labelled ZD6126 at 200 mgkg(-1). QWBA analysis showed that drug-related material was widely distributed to the tissues and tumour. In the majority of tissues, concentrations of radioactivity were highest at 15 min and declined rapidly thereafter. The tumour-to-plasma ratio was 0.6:1 at 0.25 h and increased to 6:1 at 48 h, indicating that drug-related material persisted in the tumour longer than in plasma. ZD6126, a phosphate ester, is rapidly hydrolysed to ZD6126 phenol, the active metabolite. The major metabolite in plasma (36% of the sample radioactivity) and all tumour samples (58-83% of the sample radioactivity) was confirmed as ZD6126 phenol. Extensive tumour necrosis was noted by 24h, which was still evident at 48 h, although there was some evidence of tumour regrowth.

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