Phase I study of the Aurora B kinase inhibitor barasertib (AZD1152) to assess the pharmacokinetics, metabolism and excretion in patients with acute myeloid leukemia.
Cancer Chemother Pharmacol
; 70(3): 461-9, 2012 Sep.
Article
en En
| MEDLINE
| ID: mdl-22864876
ABSTRACT
PURPOSE:
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Organofosfatos
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Quinazolinas
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Leucemia Mieloide Aguda
/
Proteínas Serina-Treonina Quinasas
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cancer Chemother Pharmacol
Año:
2012
Tipo del documento:
Article
País de afiliación:
Reino Unido