Pharmacokinetic/pharmacodynamic-based decision making in the development of MK-0888, a VEGFR-2/FLT-3 kinase inhibitor.
Cancer Chemother Pharmacol
; 75(2): 333-42, 2015 Feb.
Article
en En
| MEDLINE
| ID: mdl-25523287
ABSTRACT
PURPOSE:
MK-0888 is an investigational VEGFR-2 inhibitor with demonstrated potent in vitro enzyme activity. Clinical investigation in healthy volunteers and cancer patients was undertaken to evaluate its pharmacokinetic properties and early safety profile. Early data were used to guide whether further clinical development was warranted.METHODS:
Five phase I studies were conducted. Studies 1-4 were conducted in healthy male volunteers and examined safety and pharmacokinetics across a dose range of 0.5-100 mg. Single-dose and limited multiple-dose escalations were performed. Three formulations and food effect were assessed. Study 5 was a dose escalation study in cancer patients, evaluating pharmacokinetics and safety at doses of 6-100 mg administered up to twice daily.RESULTS:
Safety MK-0888 was generally well tolerated in healthy volunteers at single doses up to 100 mg and in cancer patients at doses up to 100 mg twice daily. Pharmacokinetics After single-dose administration, MK-0888 was readily absorbed with a T(max) of 4-5 h and a half-life of 11.3-22.7 h. AUC, C(max), and C(24h) increased in a slightly less than dose proportional manner. With longer duration multiple-dose administration (2 weeks), trough concentrations decreased from Day 2 at doses of 50 mg twice daily and higher, suggestive of autoinduction of metabolism. The efficacious trough pharmacokinetic target was not attained at steady state.CONCLUSIONS:
The pharmacokinetic behavior of MK-0888 does not support continued development. The early pharmacokinetic profile of the compound provides important information as to the probability of success of MK-0888 achieving efficacious exposures.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sulfonamidas
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Quinolonas
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Inhibidores de la Angiogénesis
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Receptor 2 de Factores de Crecimiento Endotelial Vascular
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Inhibidores Enzimáticos
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Tirosina Quinasa 3 Similar a fms
Tipo de estudio:
Clinical_trials
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Prognostic_studies
Límite:
Adult
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cancer Chemother Pharmacol
Año:
2015
Tipo del documento:
Article