Phase I Study of the Aurora B Kinase Inhibitor Barasertib (AZD1152) to Assess the Pharmacokinetics (PK), Metabolism and Excretion in Patients (pts) with Relapsed or Refractory Acute Myeloid Leukemia (AML)

Barasertib is a pro-drug that rapidly undergoes phosphatase-mediated cleavage in serum to release barasertib-hQPA (bara-hQPA), a highly potent and selective inhibitor of Aurora B kinase with antitumor activity in a broad range of hematological malignancies including AML (Löwenberg et al. Blood 2009;114:abst 2080; Tsuboi et al. Leuk Res 2011; doi: 10.1016/j.leukres.2011.04.008).

In this open-label, single-arm study (NCT01019161), AML pts received 1200 mg barasertib as a 7-day continuous iv infusion every 28 days. On Day 2 of Cycle 1 only, pts also received ¹⁴C-barasertib (250 μCi; 2-h infusion). Blood, urine and feces samples were collected at various time points during Cycle 1 to characterize the PK, metabolic and excretion profiles of barasertib.

Of the 6 pts enrolled (median age 63 years [range, 34–74]; 3 females), 5 commenced treatment and completed Cycle 1 and were therefore eligible for analysis. Of the 4 pts evaluable for disease response, 1 achieved a complete response. No new or unexpected safety findings were reported. Maximal plasma concentrations of barasertib and bara-hQPA were achieved by the first scheduled sample, taken 24 h from the start of infusion (SOI). During infusion, the mean concentration of bara-hQPA was approximately 3-fold higher than that of barasertib (Table). Following the end of infusion (EOI), plasma concentrations of barasertib fell rapidly, reaching the limit of quantification (LoQ) by 6 h after EOI, whereas bara-hQPA plasma levels declined in a triphasic manner, with low concentrations still detectable at the final sampling time point (Day 18). Bara-hQPA was extensively distributed to the tissues, with a relatively slow rate of total clearance (Table). Urine concentrations of barasertib were below LoQ at all time points. The mean urine concentrations of bara-hQPA were approximately 4–5 μg/mL during the infusion period, declining rapidly following EOI. The renal clearance (CL_R) values for bara-hQPA represent approximately 10% of the total clearance of bara-hQPA from plasma.

Overall, 72–82% of radioactivity was recovered, with approximately double the amount recovered in feces (mean = 51%) compared with urine (mean = 27%). The excretion of radioactivity in urine occurred predominantly within 72 h of ¹⁴C-SOI; however, there was large inter-patient variability in the rate of recovery of radioactivity in feces. Overall, the main excreta metabolites identified were: bara-hQPA (range, 13.2–33.7%), bara-hQPA N-acetic acid (range, 7.8–10.5%), bara-hQPA desfluoroaniline N-acetic acid (range, 5.1–9.5%), N-formyl or ethoxy bara-hQPA (range, 3.5–9.2%), and bara-hQPA desfluoroaniline (range, 1.6–5.5%). Desfluoroaniline metabolites made up a significantly larger proportion of the metabolites identified in excreta (∼15%) than in plasma (∼2%). The main pathways identified in human metabolism of barasertib were (i) cleavage of the phosphate group to form bara-hQPA, followed by oxidation, and (ii) loss of the fluoroaniline moiety to form bara-hQPA desfluoroaniline, followed by oxidation.

Pharmacokinetics of barasertib and bara-hQPA in plasma and urine

The PK profile of bara-hQPA is similar to previous studies using the same dosing regimen. The majority of clearance of bara-hQPA occurred via hepatic metabolic routes. This study is the first to characterize the metabolic pathway of barasertib in humans.

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