The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Oral Doses of RO5068760, an MEK Inhibitor, in Healthy Volunteers: Assessment of Target Suppression

RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non‐adenosine triphosphate (ATP)–competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy...

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Vydáno v:	Journal of clinical pharmacology Ročník 50; číslo 12; s. 1397 - 1405
Hlavní autoři:	Lee, Lucy, Niu, Huifeng, Goelzer, Petra, Rueger, Ruediger, Deutsch, Jonathan, Busse-Reid, Rachel, DeSchepper, Stefanie, Blotner, Steve, Barrett, Joanne, Weissgerber, Georges, Peck, Richard
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Oxford, UK Blackwell Publishing Ltd 01.12.2010 SAGE Publications Wiley Subscription Services, Inc
Témata:	Adolescent Adult Aged Biomarkers - metabolism clinical pharmacology clinical trials Colorectal cancer Dose-Response Relationship, Drug Double-Blind Method Drug Evaluation, Preclinical - methods Extracellular Signal-Regulated MAP Kinases - metabolism Half-Life Humans Imidazolidines - blood Imidazolidines - pharmacokinetics Imidazolidines - pharmacology Imidazolidines - toxicity Intestinal Absorption Leukocytes, Mononuclear - drug effects Leukocytes, Mononuclear - metabolism Male MAP Kinase Signaling System - drug effects Metabolic Clearance Rate Middle Aged Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Models, Biological oncology pharmacodynamics pharmacokinetics and drug metabolism Phenylbutyrates - blood Phenylbutyrates - pharmacokinetics Phenylbutyrates - pharmacology Phenylbutyrates - toxicity Phosphorylation - drug effects Protein Kinase Inhibitors - blood Protein Kinase Inhibitors - pharmacokinetics Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - toxicity Tetradecanoylphorbol Acetate - analogs & derivatives Tetradecanoylphorbol Acetate - pharmacology Young Adult
ISSN:	0091-2700, 1552-4604, 1552-4604
On-line přístup:	Získat plný text
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Popis
Shrnutí:	RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non‐adenosine triphosphate (ATP)–competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy volunteers. All participants received a single dose followed by 48 hours of pharmacokinetics, pharmacodynamics, and safety/tolerability assessments. The pharmacodynamics were measured by changes in ERK phosphorylation (pERK) in peripheral blood mononuclear cells, ex vivo stimulated by phorbol 12‐myristate 13‐acetate (PMA). Forty‐eight participants received 6 doses (50, 100, 200, 400, 600, 800 mg). RO5068760 was well tolerated up to 800 mg. There were no clinically significant safety findings, including laboratory, electrocardiogram, ophthalmological assessment, and fecal occult blood tests. Of the total 13 adverse events (n = 12), 11 were mild, 2 were moderate, and none were severe, and only 5 were considered by the investigator as possibly related to treatment. RO5068760 was absorbed with a tmax of 2 hours. Disposition appeared to be biphasic with a terminal elimination t1/2 of 5 to 9 hours. The variability was moderate to high, ranging from 38% to 62% for Cmax and 41% to 69% AUC. Within the dose range tested, pERK inhibition was relatively modest with a mean maximal pERK suppression of 55%.
Bibliografie:	ArticleID:JCPH5078 ark:/67375/WNG-TFWXGGNP-8 istex:61C56EE190891C44E1557B84D077682789019295 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3
ISSN:	0091-2700 1552-4604 1552-4604
DOI:	10.1177/0091270010361254