Sustained exposure to the investigational Kisspeptin analog, TAK-448, down-regulates testosterone into the castration range in healthy males and in patients with prostate cancer: results from two phase 1 studies.
J Clin Endocrinol Metab
; 99(8): E1445-53, 2014 Aug.
Article
em En
| MEDLINE
| ID: mdl-24762108
ABSTRACT
BACKGROUND/OBJECTIVE:
Kisspeptin-54, an endogenous naturally occurring ligand of the G protein-coupled receptor-54, stimulates GnRH-gonadotropin secretion and suppresses metastases in animal models of cancer but is subject to rapid degradation and inactivation. TAK-448 is an investigational oligopeptide analog of the fully active 10-amino acid C terminus of kisspeptin-54. This phase 1 study evaluated the safety, pharmacokinetics, and pharmacodynamics of TAK-448 in healthy subjects and patients with prostate cancer (PC).DESIGN:
Healthy subjects aged 50 years or older received TAK-448 sc as a single-bolus or 2-hour infusion (0.01-6 mg/d; part A) and as a 14-day sc administration (0.01-1 mg/d; part B). In a subsequent, open-label, phase 1 study in PC patients aged 40-78 years, TAK-448 was given as a 1-month depot formulation.RESULTS:
Eighty-two healthy subjects received TAK-448; 30 received placebo. Grades 1-2 adverse events were reported in 26% of subjects during TAK-448 treatment. All dosing regimens resulted in dose-proportional exposures. The maximum observed plasma concentration occurred after 0.25-0.5 hours, and median terminal elimination half-life was 1.4-5.3 hours. T increased approximately 1.3- to 2-fold by 48 hours after a single bolus or 2 hour injections, whereas during the 14-day infusion, at doses above 0.1 mg/d, T dropped to below-baseline values by 60 hours and reached a subsequently sustained below-castration level by day 8. In PC patients, T decreased to less than 20 ng/dL in four of five patients dosed with 12 or 24 mg TAK-448 sc-depot injections. The prostate-specific antigen decreased greater than 50% in all patients dosed with 24 mg.CONCLUSIONS:
Continuous TAK-448 infusion was well tolerated by healthy males and resulted in sustained T suppression. Depot injection in patients with PC similarly reduced T and resulted in prostate-specific antigen responses.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Testosterona
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Orquiectomia
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Drogas em Investigação
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Kisspeptinas
Tipo de estudo:
Clinical_trials
Limite:
Adult
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Aged
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article