title: Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia.
abstract: OBJECTIVE
  Barasertib (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.
  
  
  METHODS
  Five 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 [(14)C]-barasertib. Blood, urine and feces samples were collected at various time points during Cycle 1. Safety and preliminary efficacy were also assessed.
  
  
  RESULTS
  Barasertib-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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: The Christie NHS Foundation Trust, Manchester, UK. mike.dennis@christie.nhs.uk
authors.forename: Mike
authors.initials: M
authors.lastname: Dennis
authors.forename: Michelle
authors.initials: M
authors.lastname: Davies
authors.forename: Stuart
authors.initials: S
authors.lastname: Oliver
authors.forename: Roy
authors.initials: R
authors.lastname: D'Souza
authors.forename: Laura
authors.initials: L
authors.lastname: Pike
authors.forename: Paul
authors.initials: P
authors.lastname: Stockman
mesh_terms: D000328:Adult; D000368:Aged; D064107:Aurora Kinase B; D064127:Aurora Kinases; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010755:Organophosphates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011355:Prodrugs; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; D010755:Organophosphates; D011355:Prodrugs; D011799:Quinazolines; C531556:AZD 1152-HQPA; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases