Exposure-Response Assessment of Enzalutamide and Its Major Metabolites in a Real-World Cohort of Patients with Metastatic Castration-Resistant Prostate Cancer.
Pharmacotherapy
; 39(12): 1137-1145, 2019 12.
Article
em En
| MEDLINE
| ID: mdl-31596947
ABSTRACT
STUDY OBJECTIVE:
Enzalutamide is an oral agent for the treatment of metastatic castration-resistant prostate cancer (mCRPC); N-desmethyl enzalutamide is its active metabolite, which has clinically relevant anti-androgen capacities similar to enzalutamide, and carboxylic acid enzalutamide is an inactive metabolite. The aim of our study was to investigate the relationship between enzalutamide and N-desmethyl enzalutamide exposure and treatment response in a real-world cohort of patients with mCRPC.DESIGN:
Retrospective, observational, pharmacokinetic study.SETTING:
Outpatient clinic at a tertiary cancer center in Amsterdam, the Netherlands. PATIENTS Sixty-five patients with mCRPC who were treated with enzalutamide 160 mg daily and had at least one steady-state enzalutamide plasma concentration between May 2015 and June 2018; of these patients, 38 were prostate-specific antigen (PSA) responders and 27 were nonresponders. MEASUREMENTS AND MAINRESULTS:
Plasma concentrations, determined by using liquid chromatography with tandem mass spectrometry (LC-MS/MS), were compared between PSA responders and nonresponders. Three clinical end points were evaluated separately in this study PSA-independent progression-free survival (PFS), time to PSA progression (TTPP), and rate of PSA response (defined as ≥ 50% decrease in PSA level from baseline). Enzalutamide toxicity was defined as discontinuation due to adverse events, dose reductions due to adverse events, or temporary treatment interruption. For these analyses, plasma concentrations of enzalutamide and N-desmethyl enzalutamide were divided into quartiles. Mean ± SD plasma concentrations in the 65 patients were as follows enzalutamide 11.2 ± 2.8 µg/ml, N-desmethyl enzalutamide 9.9 ± 2.9 µg/ml, and carboxylic acid enzalutamide 6.1 ± 4.3 µg/ml. Plasma concentrations were not significantly different in the PSA responder versus nonresponder groups for enzalutamide (11.5 vs 10.6 µg/ml, p=0.20), N-desmethyl enzalutamide (10.1 vs 9.6 µg/ml, p=0.48), and carboxylic acid enzalutamide (6.5 vs 5.5 µg/ml, p=0.34). Univariate and multivariate analyses did not show a relationship between plasma concentrations and PSA-independent PFS, TTPP, or toxicity.CONCLUSION:
This study confirmed that enzalutamide plasma concentrations were not related to PSA-independent PFS, TTPP, or toxicity in patients with mCRPC, and demonstrated that plasma concentrations of its major metabolites were also not associated with treatment response. Based on these findings, there is no role for therapeutic drug monitoring of enzalutamide in patients with mCRPC in daily practice.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Feniltioidantoína
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Calicreínas
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Antígeno Prostático Específico
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Neoplasias de Próstata Resistentes à Castração
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Antineoplásicos
Tipo de estudo:
Etiology_studies
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Incidence_studies
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Observational_studies
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Risk_factors_studies
Limite:
Aged
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Aged80
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Pharmacotherapy
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Holanda